SK10012003A3 - Quinazolines as inhibitors MMP-13, process of preparation and use thereof - Google Patents

Abstract

A compound selected from those of formula (I): in which: R1 represents a group selected from hydrogen, amino, alkyl, alkenyl, aminoalkyl, aryl, arylalkyl, heterocycle, and cycloalkylalkyl, optionally substituted, W represents oxygen, sulphur, or =N-R', in which R' is as defined in the description, X1, X2 and X3 represent nitrogen or -C-R6 in which R6 is as defined in the description, Y represents oxygen, sulphur, -NH, or -N(C1-C6)alkyl, Z represents oxygen, sulphur, -NR7 in which R7 is as defined in the description, and optionally carbon atom, n is an integer from 1 to 8 inclusive, Z1 represents -CR8R9 wherein R8 and R9 are as defined in the description, A represents aromatic or non-aromatic, heterocyclic or non-heterocyclic ring system, m is an integer from 0 to 7 inclusive, the group(s) R2 is (are) is as defined in the description, R3 represents hydrogen, alkyl, alkenyl, alkynyl, or a group of formula: in which Z2, B, R5, P and q are as defined in the description, optionally, the racemic forms thereof, isomers thereof, N-oxydes thereof, and the pharmaceutically acceptable salts thereof, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix metalloprotease.

Description

Technical field

The present invention relates to novel substituted quinazolines which are suitable for the preparation of therapeutic agents for the treatment of diseases involving treatment with matrix metalloprotease-13 (MMP-13) inhibitors. These therapeutic agents are particularly useful for the treatment of certain inflammatory diseases, such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative diseases, such as cancer.

BACKGROUND OF THE INVENTION

Matrix metalloproteases (MMPs) are enzymes that are involved in restoring extracellular matrix tissue, such as cartilage, tendon, and joints. MMPs cause destruction of extracellular matrix tissue that is compensated for by its simultaneous regeneration in a non-pathological physiological state.

Under normal physiological conditions, the activity of these extremely aggressive peptidases is controlled by specialized proteins that inhibit MMPs, such as tissue metalloprotease inhibitors (TIMPs).

The local balance of MMP and TIMP activities is critical in restoring the extracellular matrix. Changes in this equilibrium, which lead to an overexpressing activity of MMPs relative to the inhibitor, induce pathological cartilage destruction, which mainly occurs in rheumatoid arthritis and osteoarthritis.

Pathological conditions undergo irreversible degradation of the articular cartilage, a case of rheumatoid diseases such as

01-1699-03-Ce rheumatoid arthritis or osteoarthritis. In these diseases, the cartilage degradation process predominates, leading to tissue destruction and consequently to loss of function.

To date, at least twenty different matrix metalloproteases have been identified, which are divided into four subgroups, namely collagenases, gelatinases, stromelysins and membrane-type MMP (MT-MMP).

Matrix metalloprotease-13 MMP-13 is a collagenase-type MMP that forms the predominant collagenase found in osteoarthritis, during which the chondrocyte controls cartilage destruction.

There is a need in the art for new MMP inhibitors, more specifically MMP-13 inhibitors, to prevent and / or correct imbalances in restoring extracellular matrix tissue in diseases such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease , psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), aging-related macular degradation (ARMD), and cancer.

MMP inhibiting compounds are known. Most MMP inhibitors are not selective for single MMPs, for example, as described by Montana and Baxter (2000) or Clark et al. (20002).

There is also a need in the art for new inhibitors that are active on matrix metalloprotease-13 in order to enrich the therapeutic arsenal that can be used in the treatment of diseases associated with destruction of extracellular matrix and cancer.

01-1699-03-CE

SUMMARY OF THE INVENTION

The present invention relates to substituted quinazoles of formula I:

where:

R ¹ is a group selected from the group consisting of

- a hydrogen atom, an amino group;

- (C 1 -C 6) alkyl, (C 3 -C 6) alkenyl, (C 3 -C 6) alkynyl, (C 1 -C 6) monoalkylaminoalkyl, (C 1 -C 6) alkylaminoalkyl group (C 6 -C 6) aryl, aryl, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl, heterocyclic, and (C 3 -C 6) cycloalkylalkyl (C 1 -C 6) -alkyl wherein these groups are unsubstituted or substituted by one or more groups, which may be the same or different and are selected from the group consisting of amino, (C 1 -C 6) alkyl, cyano, (C 1 -C 6) haloalkyl, C (= O) OR ⁴ , OR ^4, and SR ⁴ wherein R ⁴ is hydrogen or (1-6C) alkyl,

01-16S9-03-CE

W is an oxygen atom, a sulfur atom or a group = N-R ', wherein R' is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a cyano group,

X ¹ , X ² and X ³ are, independently of one another, a nitrogen atom or a group -CR ⁶ , wherein R ⁶ is a group selected from the group consisting of hydrogen, C 1 -C 6 alkyl, amino, C 1 -C 6 monoalkylamino carbon atoms, a dialkylamino group having from 1 to 6 carbon atoms in each alkyl moiety, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom, provided that no more than two of X ¹ , X ² and X ³ are simultaneously nitrogen atom,

Y is a group selected from oxygen, sulfur, -NH and -N-C 1 -C 6 -alkyl,

Z is:

- oxygen, sulfur,

- or -NR ⁷ where R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl and when Y is an oxygen atom, a sulfur atom, or an -N-alkyl group having 1 to 6 carbon atoms, Z is optionally a carbon atom which is unsubstituted or substituted by a group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, aryl, arylalkyl having 1 to 6 carbon atoms in the alkyl moiety, aromatic

01-1699-03-Ce or a non-aromatic heterocyclic group or cycloalkyl group, n is an integer from 1 to 8 inclusive,

Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, halogen , amino, OR ⁴ , SR ⁴ or C (= O) OR ⁴ , wherein R ⁴ 'is hydrogen or (C 1 -C 6) alkyl and

if n is higher than or equal to two, the hydrocarbon chain Z ¹ optionally contains one or more multiple bonds.

- and / or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, or a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms .

- if one of the carbon atoms of the hydrocarbon chain of Z ¹ is replaced by a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, then the -C (Y) -Z- group may be absent in the compound of formula I,

A is a group selected from the group consisting of:

an aromatic or non-aromatic, 5- or 6-membered monocycle containing 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; and

01-1699-03-Ce two-aromatic bicycle! or non-aromatic, five-membered or six-membered rings, which may be the same or different, containing 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, m is an integer from 0 to 7 inclusive, the group (s) R ² may be same or different, is (are) selected from the group consisting of C 1 -C 6 alkyl, halogen, -CN, -NO ₂ , -SCF ₃ , -CF ₃ , -OCF ₃ , -NR ^{1 O U} R, -OR ^10, -SR ^I0, -SOR ¹⁰ group, a group -SO 2 R ^10, - (CH 2) _a SO ₂ NR ¹⁰ R ^u -X ⁵ (CH 2) k C (= 0) OR ^10, (CH 2) _k C (= 0) OR ^10, -X ⁵ _{(CH2) k} C (= 0) NR ¹⁰ R ¹¹ group,

- (CH _{2) k} C (= 0) NR R ^{1 O, U,} and -X ⁴ -R ¹² wherein:

- X ⁵ is selected from the group consisting of oxygen, sulfur optionally substituted by one or two oxygen atoms, and nitrogen substituted with hydrogen or C 1 -C 6 alkyl,

- k is an integer from 0 to 3 inclusive,

- R ¹⁰ and R ¹¹ , which may be the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms,

X ⁴ is a group selected from the group consisting of a direct bond, -CH _{2 -Z,} an oxygen atom, a sulfur atom optionally substituted by one or more oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

- R ¹² is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, 5- or 6-membered cyclic group,

01-1699-03 -C

Ί which is unsubstituted or substituted by one or more groups, which may be the same or different, and are selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, hydroxyl and amino, and, if the ring is heterocyclic, contains 1-4 heteroatoms selected from nitrogen, oxygen and sulfur;

R ³ is a group selected from the group consisting of:

- a hydrogen atom,

- (C 1 -C 6) alkyl, (C 3 -C 6) alkenyl, (C 3 -C 6) alkynyl, which groups are unsubstituted or substituted by one or more groups which may be the same or different and are selected from the group consisting of amino, cyano, having 1 to 6 carbon atoms, haloalkyl, cycloalkyl, -C (= 0) NR R ^{1 O V,} and a group SR ¹⁰ wherein R ¹⁰ and R ^11, the group> io

-C (= O) OR ¹⁰ , the group OR, may be the same or different, are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and a group of formula (R) wherein p is an integer from 0 to 8 inclusive,

Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, phenyl,

C 1 -C 6 haloalkyl, halogen, amino, OR ⁴ , SR ', and -C (= O) OR ⁴ , wherein R ⁴ is hydrogen or C 1 -C 6 alkyl; up to 6 carbon atoms, and

- if p is greater than or equal to two, the hydrocarbon chain Z ² optionally contains one or more multiple bonds,

- and / or the carbon atoms in the Z ² hydrocarbon chain may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, or group,

B is a group selected from the group consisting of:

- an aromatic or non-aromatic 5- or 6-membered monocycle containing 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and a bicyclic consisting of two aromatic or non-aromatic, 5- or 6-membered rings, which may be the same or different, containing 0 to 4 from nitrogen, oxygen and sulfur, q is an integer from 0 to 7 inclusive, the group (s) R ⁵ which may be the same or different is (are) selected from the group consisting of an alkyl group containing 1 to 6 atoms carbon, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ¹⁵ R ¹⁰ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁵ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S (O) klR ¹⁵ , -SO ² N (R) ¹⁵ ) (CK2) _k2 NR * 'R ¹ ', - (CH ₂ ) group _to SO ₂ NR ¹⁵ R ¹⁰ , s scale

01-1699-03-CE

-X ⁷ (CH 2) k C (= O) OR ¹⁵ , - (CH 2) _k C (= O) OR ¹⁵ , -C (= O) O- (CH 2) k ² NR ¹⁵ R ¹⁶ , -C (= O) O- (CH 2) _{k 2} C (= O) OR ¹⁵ , group

-X ⁷ (CH 2) k C (= O) NR ¹⁵ R ¹⁵ , - (CH 2) _k C (= O) NR ¹⁵ R ¹⁶ , group

-R ¹⁹ -C (= O) OR ¹⁵ , -X ⁶ -R ²⁰ , and -C (= O) -R ²¹ -NR ¹⁵ R ¹⁵ , wherein

- X ⁷ is selected from oxygen, sulfur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or C 1 -C 6 alkyl,

- k is an integer from 0 to 3 inclusive,

- kl is an integer from 0 to 2 inclusive,

- k2 is an integer of 1 to 4 inclusive,

- R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms,

R ¹⁸ is selected from the group consisting of C 1 -C 6 alkyl, -R ²¹ -NR ¹⁵ R ¹⁶ , R ²¹ -NR ¹⁵ -C (= O) -R ²¹ -NR ¹⁶ R ¹⁷ , and -C (= O) OR ²¹ -NR ¹⁵ R ¹⁶ wherein R ²¹ is a linear or branched alkylene group having 1 to 6 carbon atoms, and R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above,

- R ¹⁹ is a cycloalkyl group having 3 to 6 carbon atoms,

- X ⁶ is selected from the group consisting of a direct bond, -CH ₂ -, an oxygen atom, a sulfur atom optionally substituted by one or two oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms,

01-1699-03-CE

- R ²⁰ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups which may be the same or different, selected from the group consisting of alkyl of 1 to 5 halogen atoms, hydroxyl a group, tetrazole, amino, is a hydrogen atom or an alkyl group of 6 carbon atoms, and when the ring is heterocyclic, it contains from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, carbon, cyano, oxos and oxos;

-C (= O) OR ⁴ , wherein R ⁴ containing 1 and i 0, provided that when X is a nitrogen atom, X may not be substituted by a methyl or NH-CH _{3 group} , or its racemic forms, isomers thereof, N-oxides and their pharmaceutically acceptable salts.

The compounds of the present invention are useful as inhibitors, in particular as selective inhibitors, of the matrix metalloprotease-13 (MMP-13) enzyme.

The present invention also relates to compounds used in particular as intermediates for the synthesis of compounds of formula I. These intermediates have the formula III:

(III) wherein R ³ has the same meaning, of the general formula I.

as defined for the compounds

01-1699-03 -C

The present invention also relates to compounds used in particular as intermediates for the synthesis of compounds of formula I having the formula IV:

wherein R ¹ and R ³ have the same meaning as previously defined for the compounds of formula I.

The present invention also relates to a process for the preparation of a compound of formula I, wherein

R ² , R ³ , Z ¹ , A, m and n are the same as defined for the compounds of formula I

- X ¹ , X ² , X ³ are each -CR ⁶ wherein R ⁶ is hydrogen,

- Y is an oxygen atom,

- Z is -NR ⁷ where R ⁷ is as defined for compounds of formula I,

and W is an oxygen atom.

The method is characterized in that it comprises reacting a compound of formula II:

MeO (Π)

01-1693-03-Ce with pyridine and a compound of formula V:

O = C = NR ³ (V) wherein R ^J is as defined above for a compound of Formula I to give a compound of Formula VI:

(VI) wherein R ³ is as defined above, followed by reaction of a compound of general formula in the presence of lithium hydroxide to give a general formula III, wherein R ³ is as defined above.

of formula VI of the compound

(ΠΓ>

In the next step of the synthetic process, the compound of formula III obtained above is reacted in the presence of an acid activator such as O - [(ethoxycarbonyl) quanomethyleneaminol-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TOTU) with a compound of formula VII:

01-1699-03-CE

(R ² ), l ·

A '). NH (Z ¹ ).

(VK) wherein R ⁷ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are the same as defined for compounds of formula I to give a compound of formula I wherein R ¹ is hydrogen, X ¹ , X ² and X ³ are each -CR ⁶ wherein R ⁶ is hydrogen, Y is oxygen, Z is NR ⁷ , W is oxygen, and A, R ² , Z ¹ , n and n are the same as defined above.

In particular, when W is an oxygen atom, Y is an oxygen atom and Z is an oxygen atom, a compound of formula I corresponding to this definition may be obtained by reaction of a compound of formula III:

(H1) wherein R ³ is as defined for a compound of formula I with a compound of formula XVI:

(XVI)

Wherein Z ¹ , A, R ² , n and m are the same as defined for the compound of formula I, to obtain a compound of formula XVII:

wherein A, R ² , R ³ , Z ¹ , m and n are a compound of the formula -CR ⁶ , wherein R ⁶ is a hydrogen atom as defined for I and X ¹ , X ² , and X ³ are each a group then reacting a compound of formula XVII in the presence of a base with a compound of formula VIII, XR ¹ , wherein R ¹ is as defined for a compound of formula I and X is a leaving group such as a halogen atom, to give a compound of formula I wherein X ¹ , X ² and X ³ are each -CR ⁶ , where R ⁶ is as defined above, W is oxygen, Y is oxygen, Z is oxygen and R ¹ , R ² , R ³ , Z ¹ ,

A, n and m are as defined above.

In particular, when X ² and X ³ are each -CR ⁶ , where R ⁶ is hydrogen, X ¹ is nitrogen, Z is oxygen and Y is oxygen, compounds of formula I corresponding to this definition can be prepared by reacting a compound of formula XIX:

01-1699-03-X (XIX)

with pyridine and a compound of formula O = C = NR ³ (V), wherein R ³ is as defined for a compound of formula I to give a compound of formula XX:

(XX) wherein R ³ is as defined above, then the compound of formula XX is reacted in the presence of potassium permanganate to give a compound of formula XXI:

(XXI) wherein R ³ is as defined above, then the compound of the general formula in the presence of SOCl ₂ and chloroform of the formula XXII:

of formula XXI is reacted to obtain a compound of formula XXI

01-1699-03-Ce (XXII) where R ³ is the same,

as defined above, then the compound of formula XXII is reacted with a compound of formula XVI:

(R)

AJ 1, ΟΗ (xvi) wherein A, R ² , Z ¹ , n and m are as defined for a compound of formula I to give a compound of formula I:

(XXIV) wherein A, R ^2, R ^3, Z ¹ and n are the same as defined above, X ² and X ³ are each ^p-CR, wherein R ⁶ is as defined above, and R ³ are the same as as defined for the compound of formula tf

I.

The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable excipient.

The present invention also relates to the use of a compound of formula I for the preparation of a medicinal product

01-1699-03-Ce for the treatment of a disease or condition comprising treatment by inhibition of matrix metalloprotease, and more particularly type-13 matrix metalloprotease (MMP-13).

The present invention also relates to a method of treating a disease or condition comprising treatment by inhibiting matrix metalloprotease, and more particularly MMP-13, wherein said method comprises administering to the patient an effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The Applicant has identified novel compounds that are matrix metalloprotease inhibitors and more specifically novel compounds that are MMP-13 inhibitors according to the present invention.

Thus, one object of the present invention is a substituted quinazoline of formula I:

wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , W, Y, Z, Z ¹ , n and m are as defined above for the compound of formula I, optionally their racemic forms, their isomeric forms, their N- oxides and their pharmaceutically acceptable salts.

In particular, the present invention relates to compounds of formula I wherein:

R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1

C 1 -C 6 -C 6 carbon atoms or a 3 to 6 membered cycloalkylalkyl group containing from 1 to 6 carbon atoms in the alkyl moiety,

W is an oxygen atom or a sulfur atom,

X ¹ is a nitrogen atom or a group -CR ⁵ wherein R ⁶ is a hydrogen atom,

X ² and X ³ are each -CR ⁶ wherein R ⁵ is hydrogen,

Y is an oxygen atom,

Z is an oxygen atom or a group -NR ⁷ wherein R ⁷ is a hydrogen atom.

The present invention also relates to compounds of formula I wherein:

n is an integer from 1 to 6 inclusive,

Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ is hydrogen and R ⁹ is hydrogen or methyl, and

- if n is greater than or equal to 2, the hydrocarbon chain of Z ¹ optionally contains a double bond,

- or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom or a sulfur atom which is unsubstituted or substituted by one or more oxygen atoms,

A is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, piperidyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, benzofurazanyl, 2,1, 3-benzothiadiazolyl and indolyl,

01-1699-03-Ce m is an integer of 0 to 7 inclusive, the group (s) R ² , which may be the same or different, is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ¹⁰ R ^11, -OR ^10, -SR ^10, -SO 2 R ¹⁰ group, - (CH 2) ^u R ¹⁰ kSO2NR group - X ⁵ (CH 2) _k C - (= O) OR ¹⁰ , - (CH 2) k C (= O) OR ¹⁰ , -X ⁵ (CH 2) _k C (= O) NR ¹⁰ R ¹¹ , - (CH) _{2) a} C (= 0) NR ¹⁰ R ^n, and -X ⁴ -R ¹² wherein:

X ⁵ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive,

R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms,

X ⁴ is -CH ₂ -, or an oxygen atom,

R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, halogen, hydroxyl and amino.

The present invention also relates to compounds of formula I wherein R ³ is hydrogen, alkyl of 1 to 6 carbon atoms, or a group of the formula:

where p is an integer from 0 to 3 inclusive,

01-1699-O3-CE

Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, methyl or phenyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ² or contains one double bond,

- or one of the carbon atoms in the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms, or a carbonyl group,

B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl a group, a naphthyl group and an indolyl group, q is an integer from 0 to 3 inclusive;

the group (s) R ⁵ , which may be the same or different, is (are) selected from the group consisting of (C 1 -C 6) alkyl, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ^1:> R ¹⁰ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) ¹⁵⁾ SO 2 R ^16, -N (SO 2 R ⁱ⁵⁾ 2, -OR ^15, -S (0) KLR ^15, a group -SO 2 N (R ¹⁵⁾ (CH 2) _{k 2} NR ¹⁶ R ⁱ ', the - (CK2 ) kSO2 NR ¹⁵ R ^1c , -X ⁷ (CH 2) _k C (= O) OR ¹⁵ , - (CH 2) k C (= O) OR ¹⁵ , -C (= O) O- (CH 2) _{k 2} NR ¹⁵ R ^1D , -X ⁷ (CH ₂ ) _{k to} C (= O) NR ¹⁵ R ^10, and

- (CH _{Z) a} C (= 0) NR ¹⁵ R ^16, wherein

01-1699-03 -C

X 'is a group selected from oxygen, sulfur or NH,

- k is an integer from 0 to 3 inclusive,

- kl is an integer from 0 to 2 inclusive,

- k2 is an integer of 1 to 4 inclusive,

R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

The present invention more preferably relates to compounds of formula I wherein

R ¹ is selected from the group consisting of:

hydrogen, amino, (1-6C) alkyl, (3-6C) alkenyl, (3-6C) alkynyl, (C1-6C) monoalkylaminoalkyl, (C1-6C) alkyl) C 1 -C 6 alkyl, aryl, aryl C 1 -C 6 arylalkyl, heterocyclic, and C 3 -C 6 cycloalkylalkyl C 1 -C 6 alkyl wherein these groups are unsubstituted or substituted once or a plurality of groups which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, -C (= O) OR ⁴ , OR ⁴ and SR ⁴ ,

Wherein R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

W is an oxygen atom, a sulfur aroma or an N-R 'group, wherein R' is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a cyano group,

X ¹ is a nitrogen atom or a group -CR ⁶ wherein R ⁶ is a hydrogen atom,

X ² and X ³ are, independently of one another, a -CR ⁶ group, wherein R 0 is a group selected from the group consisting of hydrogen, C 1 -C 6 alkyl, amino, hydroxyl, and halogen,

Y is an oxygen atom,

Z is an oxygen atom or a group -NR ⁷ , wherein R ⁷ is a group selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, n is an integer of 1 to 6 inclusive,

Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and hydroxyl, and when n is an integer above or is equal to 2, the hydrocarbon chain of Z ¹ optionally contains one or more multiple bonds,

- or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms or a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms,

0'-L-1699-03-Ce furyl, oxinyl,

A is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, 1,3-benzodioxolyl, benzodibenzothienyl, benzofuryl, benzofurazanyl, 2,1,3-benzothiadiazolyl and indolyl, m is an integer from 0 to 3 inclusive, the group (s) R ² , which may be the same or different, is selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ¹⁰ R ^11, -OR ^10, -SR ^10, -SO 2 R ¹⁰ group, - (CH 2) _a SO ₂ NR ¹⁰ R ^n, -X ⁵ ( CH ₂ ) _k C - (= O) OR ¹⁰ , - (CH 2) k C (= O) OR ¹⁰ , -X ⁵ (CH 2) _k C (= O) NR ¹⁰ R ¹¹ , - (CH ₂ ) group _a C (= 0) NR R ^{1 O U} a -X ⁴ -R ¹² wherein:

X ⁵ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive,

R ¹⁰ and R ¹¹ ', which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms,

X ⁴ is -CH ₂ -, or an oxygen atom,

R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, halogen and hydroxyl,

01-1699-03 -C

R ³ is a group selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and a group of the formula wherein p is an integer from 0 to 6 inclusive,

Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are each independently hydrogen, C 1 -C 6 alkyl, and hydroxyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ^{2 is} optionally Contains one or more multiple bonds

- or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms,

B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl a group, a naphthyl group and an indolyl group, q is an integer from 0 to 3 inclusive, the group (s) R ⁵ which may be the same or different is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, CN, NO ₂ ,

01-1699-03-Ce CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= 0) OR ¹⁶ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S (O) kiR ¹⁵ , -SO ² N (R ¹⁵ ) (CH 2) _{k 2} NR ¹⁶ R ^17, - (CH 2) kSO2NR ¹⁵ R ^16, -X ⁷ (CH 2) _k C (= 0) OR ^15, - (CH 2) k C (= 0) OR ^15, -C (= O) 0- (CH 2) _{k 2} NR ¹⁵ R ¹⁶ , -X ⁷ (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ ,

- (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ and -X ⁶ -R ²⁰ where

- X ⁷ is a group selected from oxygen, sulfur or NH,

- k is an integer from 0 to 3 inclusive,

- kl is an integer from 0 to 2 inclusive,

- k2 is an integer of 1 to 4 inclusive,

- R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms,

- X ⁶ is a group selected from the group consisting of a single bond, -CH ₂ -, an oxygen atom or a sulfur atom optionally substituted by one or two oxygen atoms,

- R ²⁰ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of alkyl having 1 to 6 carbon atoms, atom halogen, hydroxyl and amino, and when the ring is heterocyclic, contains 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.

01-i 699-03-Ce

The present invention also relates to compounds of formula I wherein:

R ¹ is selected from the group consisting of hydrogen, monoalkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, alkyl having 1 to 6 carbon atoms, alkenyl containing (C 3 -C 6) alkynyl, (C 3 -C 6) alkynyl, (C 1 -C 6) aryl, (C 1 -C 6) arylalkyl, and (C 1 -C 6) cycloalkylalkyl,

W is an oxygen atom or a sulfur atom,

X ¹ is nitrogen or -CH,

X ² and X ³ are -CH,

Y is a group selected from the group consisting of oxygen, sulfur, -NH, and -N-alkyl of 1 to 6 carbon atoms,

Z is O or -NH, n is an integer from 1 to 3 inclusive,

Z ¹ is -CR ^S R ⁹ wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxyl; and

- if n is higher than or equal to two, the hydrocarbon chain Z * optionally contains one double bond,

01-1699-03 -C

- or one of the carbon atoms of the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two carbon atoms, or an -NH group,

A is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl a group, a naphthyl group and an indolyl group, m is an integer of 0 to 3 inclusive, the group (s) R ² which may be the same or different is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, -CN, -CF 3, -OCF _3, -NR ^{1 O U} R, -OR ^10, -SR ^10, -SO 2 R ¹⁰ group, - (CH 2) _a SO ₂ NR ¹⁰ R ^u , -X ⁵ _{(CH2) a} - C (= O) OR ^10, - (CH 2) k C (= 0) OR ^10, -X ⁵ (CH 2) _k C (= 0) NR R ^{1 O U,} - (CH ₂ ) _k C (= O) NR ¹⁰ R ¹¹ and -X ⁴ -R ¹² where:

X ⁵ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive,

R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms,

X ⁴ is -CH ₂ -, or an oxygen atom,

R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of

C 1-6 16-03-03 C 1 -C 6 alkyl, halogen and hydroxyl,

R ³ is a group selected from a methyl group and a group of the formula:

where p is an integer from 0 to 3 inclusive,

Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and hydroxyl, and when p is greater than or equal to 2 , the hydrocarbon chain Z ² optionally contains one double bond,

- or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms,

B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl the group, naphthyl and indolyl, o is an integer from 0 to 3 inclusive, the group (s) R ⁵ which may be the same or different is (are) selected from the group consisting of an alkyl group containing 1

01-1699-03-C6 to 6 carbon atoms, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _to NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S ( O) klR ¹⁵ , -SO ² N (R ¹⁵ ) (CH 2) _{k 2} NR ¹⁶ R ¹⁷ , - (CH 2) k SO ² NR ¹⁵ R ¹⁶ , -X ⁷ (CH 2) _k C (= O) OR ¹⁵ , - (-) CH 2) k C (= O) OR ¹⁵ , -C (= O) O- (CH 2) _{k 2} NR ¹⁵ R ¹⁶ , -X ⁷ (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ , group

- (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ and -X ^with -R ²⁰ where

- X ⁷ is a group selected from oxygen, sulfur or NH,

- k is an integer from 0 to 3 inclusive,

- kl is an integer from 0 to 2 inclusive,

- k2 is an integer of 1 to 4 inclusive,

- R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms,

- X ⁶ is a group selected from the group consisting of a single bond, -CH ₂ -, an oxygen atom or a sulfur atom optionally substituted by one or two oxygen atoms,

- R ²⁰ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of alkyl having 1 to 6 carbon atoms, atom halogen, hydroxyl and amino, and when the ring is heterocyclic, contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

01-1699-03 -C

The present invention also relates to compounds of formula I wherein:

R ¹ is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 1 -C 6 arylalkyl, C 3 -C 6 cycloalkylalkyl C 1 -C 6 alkyl .

W is an oxygen atom,

X ¹ is -CH or N and X ² and X ³ are each -CH;

Y is an oxygen atom,

Z is O or -NH, n is an integer from 1 to 3 inclusive,

Z is a group -CR R wherein R and R are independently selected from hydrogen and methyl; and

- if n is greater than or equal to two, the hydrocarbon chain Z ¹ optionally contains one double bond,

- or one of the carbon atoms of the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two carbon atoms, or an -NH group,

A is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl and 1,3-benzodioxolyl, m is an integer from 0 to 3 inclusive,

01-1699-03 -C group (s) ^R2, which may be the same or different, is (are) selected from the group consisting of alkyl having 1 to 6 carbon atoms, halogen, -CN, -CF ₃ , -OCF ₃ , -NR ¹⁰ R ¹¹ , -OR ¹⁰ , -SR ¹⁰ , -SO ² R ¹⁰ , - (CH 2) k SO ² NR ¹⁰ R ¹¹ , -X 5 (CH ₂ ) _k C (= 0) -OR ^10, - (CH 2) k C (= 0) OR ^10, -X ⁵ (CH 2) _k C (= 0) NR R ^{1 O U} a - (CH _{2) k} C (= 0) NR ^1O R ^U where:

X ³ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive,

R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms,

R ³ is a group of the formula

where p is an integer from 0 to 3 inclusive,

Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from hydrogen and methyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ² optionally contains one double bond,

- or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms,

01-1699-O3 -C

B is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, and 1,3-benzodioxolyiová group, q is an integer from 0 to 3 inclusive, the group (s) ^R5, which may be same or different, is (are) selected from the group consisting of (C 1 -C 6) alkyl, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _to NR ¹⁵ R ¹⁰ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO ² R ¹⁵ ) 2, -OR ¹⁰ , -S (O) kiR ¹⁵ , -SO 2 N (R ¹⁵ ) (CH 2) _{k 2} NR ¹⁶ R ¹⁷ , - (CH 2) k SO ² NR ¹⁵ R ¹⁶ , -X ⁷ (CH 2) _k C (-0) OR ^15, - (CH 2) k C (= 0) OR ^15, -C (= 0) 0- (CH2) _{k 2} NR ^l0 R ^ls, -X ⁷ (CH _{2) k} C ( = O) NR ¹⁵ R ^1d and the group

- (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ where

- X ⁷ is a group selected from oxygen, sulfur or NH,

- k is an integer from 0 to 3 inclusive,

- kl is an integer from 0 to 2 inclusive,

- k2 is an integer of 1 to 4 inclusive,

R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

The present invention also relates to compounds of formula I wherein R ¹ is hydrogen or C 1 -C 6 alkyl.

01-1699-03-CE

The present invention also relates to compounds of formula I wherein W is oxygen, Y is oxygen, Z is NH, Z ¹ is methylene and n is 1.

The present invention also relates to compounds of formula I wherein X ¹ is -CH or N, and X ² and X ³ are each -CH.

The present invention also relates to compounds of formula I wherein X ¹ and X ³ are each -CH and X ² is -CH or a nitrogen atom.

The present invention is of formula I wherein X ¹ and X ³ are each also related to compounds of the general group -CH and X ² is a nitrogen atom.

compounds of the general group consisting of 1,3-benzodioxolyl equal to 0 or 1 and R ² alkoxy atom

The present invention also relates to formula I wherein A is a group selected from phenyl, pyridyl, group and benzofurazanyl, m is a group selected from the group consisting of 1 to 6 carbon atoms, hydroxyl group, halogen and thioalkoxy group containing 1 to 6 carbon atoms. up to 6 carbon atoms.

The present invention also relates to compounds of formula I wherein R ³ is a group of the formula:

where:

p equals 1,

Z ² is a methylene group,

01-1699-03 -C

B is a group selected from phenyl, pyridyl, 1,3-benzodioxolyl and benzofurazanyl, q is an integer from 0 to 2 inclusive, and R ⁵ is a group selected from halogen, CN , - (CH2) k NR ¹⁵ R ¹⁶ , -S (O) klR ¹⁵ , - (CH 2) k SO ² NR ¹⁵ R ¹⁶ , - (CH 2) _k C (= O) OR ¹⁵ , -X ⁶ -R ²⁰ and - (CH ₂ ) _k C (O) NR ¹⁵ R ¹⁶ wherein k is an integer from 0 to 1 inclusive, kl is an integer from 0 to 2 inclusive,

R ¹⁵ and R ¹⁶ , which may be the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms.

X ^b is a single bond,

R ²⁰ is a five-membered heterocyclic ring containing 3 to 4 heteroatoms selected from oxygen and nitrogen and optionally substituted with methyl or oxo.

Among the groups defined above, the following substituents are particularly preferred:

- halogen atom: F, Cl, Br, I,

an alkyl group containing or branched containing 1 carbon;

an alkoxy group containing 1 or branched containing 1 carbon;

preferably F, Br and Cl;

up to 6 carbon atoms: linear up to 6 and preferably 1 to 3 atoms up to 6 carbon atoms: linear up to 6 and preferably 1 to 3 atoms

01-1699-03 -C

alkenyl comprising 3 to 6 carbon alkyl: containing 3 to 6 a preferably 3 or 4 carbon alkyl, more preferably an allyl group; alkynyl contain an account 3 to 6 carbon alkyl: containing 3 to 6 a preferably 3 or 4 carbon alkyl, more preferably propargyl group;

an aryl group: containing 5 to 10 and preferably 5 or 6 carbon atoms;

heteroaryl: an aryl group interrupted by one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The term "interrupted" means that a heteroatom can replace a ring carbon atom. Examples of such heteroatom-containing groups include, but are not limited to, thienyl, pyridyl, benzofurazanyl;

heterocyclic group: an aromatic or non-aromatic, 5- or 6-membered monocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;

an arylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, preferably 1 to 4 carbon atoms;

a cycloalkyl group: containing 3 to 8 and preferably 3 to 6 carbon atoms;

a cycloalkylalkyl group having 1 to 6 carbon atoms in the alkyl moiety and preferably 1 to 3 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms;

a multiple bond comprises a double or triple bond.

-1699-03-CE

Preferred compounds of the present invention include those described in Examples 1 to 227 below.

More specifically, preferred compounds of the present invention are those of formula I which are:

- [6- (4-Methoxy-benzylcarbamdyl) -1-methyl-2,4-dioxo-1,4-dihyaro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid (1,3 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid -benzodioxol-5-ylmethyl) amide

4- [6- (4-Fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

1-Methyl-2,4-dioxo-3- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -benzyl] 4-methoxybenzylamide -1,2,3 4-tetrahydroquinazoline-6-carboxylic acid 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid hemicalcium salt of methyl- 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido: 3,4-d] pyrimidin-3-ylmethyl] benzoate [6- (3) -methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yimethyl] benzoic acid

1-methyl-2,4-dioxo-3- [4- (2H-tetrazol-5-yl) benzyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl-2-hydroxy- 4- [6- (4-metoxybenzyikarbamoyl) -1-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

01-1699-03 -C

3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

4- {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

2-hydroxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-4- [6- (3- methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

4-pyridylmethyl-3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylate methyl 4- {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] - 1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate

1-Methyl-3- [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

1-Methyl-3- [4- (3-methyl-1,2,4-oxadiazol-5-yl) -benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H] quinazolin-3-ylmethyl] benzoic acid

- 1 - 1 6 9 9-'3 3-Ce

1- (4- [6- (4-methoxybenzyicarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} cyclopropanecarboxylic acid

4-pyridylmethyl-3-benzyl-1-methyl-2,4-dioxo-2,3,4-tetrahydroquinazoline-6-carboxylate

3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

3- (4-Dimethylcarbamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

1-Methyl-3- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide (2-methoxypyridine) 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide 3- (3-ylmethyl) amide 4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl-3-benzyl-1-methyl- 3-Benzyl-1-methyl-2,4-dioxo-1,2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (benzo [1,3] dioxol-5-ylmethyl) -amide 3,4-tetrahydroquinazoline-6-carboxylic acid

1-Methyl-3- (4-methylcarbamoylbenzyl) -2,4-methoxybenzylamide

-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

01-1699-03 -C

3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

4- [6- (4-hydroxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-4- [6- (4-fluorobenzylcarbamoyl) - 1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

3- (4-Chlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide

1-Methyl-3- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

4-pyridylmethyl-3- (benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate methyl 4- [6- (4-methoxybenzylcarbamoyl) ) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmety1] benzoate

1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydroquinazinecarboxylic acid 4-methoxybenzylamide

3- (4-Aminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

1-Methyl-3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo

-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

01-1699-03 -C

1-Methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

1-Methyl-2,4-dioxo-3- (4-sulfamoylbenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

3- (4-Fluorobenzyl) -3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide (pyridin-4-ylmethyl) amide 1- (4-Methoxy-benzyl) -1-methyl-2,4-l-methyl-2-, 4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide -dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

2-Methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

4- {1-Methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid

3- (3-Fluoro-4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamine

4- [1-ethyl-6- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (benzo [1,3] dioxol-5-ylmethyl) 3- (Benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid amide

3- (2'-Cyanobiphenyl-4-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

01-1599-03-Ce oxo

4- [1-methyl-6- (4-methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid - {6 - [(benzofurazan-5-ylmethyl) carbamoyl 1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid methyl-2-methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2 4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

3- (4-Acetylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide (benzo [1,3] dioxol-5-ylmethyl) amide 3 - (benzo [1,3] dioxol-5-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

3- (4-Dimethylcarbamoylmethylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide benzo [1,3] dioxol-5-ylmethyl-3-benzyl -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H- quinazolin-3-ylmethyl] phenyl} acetic acid (4- {1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl (phenyl) acetic acid

3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl- {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4- 3- (3-Fluorobenzyl) -1-methyl-2,4-di-1,2,3-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} acetate (pyridin-4-ylmethyl) amide 4-tetrahydroquinazoline-6-carboxylic acid

01-1699-03 2,4-Dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 2,4-dioxo-3- (thien-2-ylmethyl) amide of

1-methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl-4- {1-methyl-2,4-dioxo- 6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate

2-Fluoro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

4- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid hemi-magnesium salt 6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid

3- [4- (N-Methylsulfonylamino) benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide ethyl-2-fluoro-4- [6 - (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide and

01-1699-03 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6 (benzo [1,3] dioxol-5-ylmethyl) amide -carboxylic acid.

The present invention also relates to pharmaceutically acceptable salts of the compounds of formula I. The pharmaceutically acceptable salts are found in J. Pharm. Sci., 1977, vol. 66: 1-19. However, the term "pharmacologically acceptable salts of compounds of formula I with a basic function" means addition salts of compounds of formula I formed from non-toxic mineral or organic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, benzoic acid, fumaric acid, toluenesulfonic acid, isethionic acid and the like. Also included in this category of compounds of the present invention are various quaternary ammonium salts of the compounds of formula I. Further, the term "pharmacologically acceptable acid-functional salts of the compounds of formula I" generally means salts of the compounds of formula I formed with non-toxic mineral or organic bases such as alkali hydroxides alkaline earth metals (sodium, potassium, magnesium and calcium), amines (dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like) or quaternary ammonium hydroxides such as tetramethylammonium hydroxide.

As mentioned above, the compounds of Formula I of the present invention are proteases and, more particularly, are inhibitors of matrix metalloin inhibitors of the MMP-13 enzyme. In this sense, their use in the treatment of diseases or conditions involving treatment by inhibition of MMP-13 is recommended. For example

-16 1-1699-03-Ce it is recommended to use the compounds of the present invention in the treatment of any disease that causes destruction of extracellular matrix tissue and most preferably diseases such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, inflammatory bowel disease psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), age-related macular degeneration (ARMD), and some cancers.

Selectivity of compounds of formula I to the enzyme MMP-13

Most of the matrix metalloprotease inhibitors described in the prior art are non-selective inhibitors that are capable of simultaneously inhibiting several matrix metalloproteases. For example, compounds such as CGS-27.023A and AG-3340 (Montana and Baxter (2000)) inhibit both MMP-1, MMP-2, MMP-3, MMP-9 and MMP-13, i.e., these compounds according to They inhibit MMPs both of the type of collagenase and of gelatinase and stromelysin.

According to the present invention, compounds of formula I have been shown to be selective MMP-13 inhibitors. "Selective MMP-13 inhibitors are compounds of formula I having an IC ₅₀ to MMP-13 of at least five times lower than an IC ₅₀ to MMP of a type other than MMP-13, and preferably at least ten, fifteen, twenty, thirty, forty times , fifty times, a hundred or a thousand times lower than an IC _{50 of} a type other than MMP-13.

MMPs other than MMP-13 are preferably matrix metalloproteases selected from MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-14.

01-1699-03 -C

In particular, it has been shown according to the present invention that the compounds of the formula I, and in particular the group of compounds exemplified in the description, have an IC ₅₀ value for MMP13 which is often thousands of times lower than their IC 50 value for other matrix metalloproteases. 1, MMP-2, MMP-3, MMP-7, MMP-9, MMP 12, and MMP-14.

As a result, the compounds of formula (I) of the present invention are particularly useful in the treatment of diseases primarily related to physiological imbalance between the MMP-13 enzymes and their natural tissue inhibitors.

Pharmaceutical compositions of the compounds of the present invention

The present invention also provides a pharmaceutical composition comprising a compound of formula I as defined above and a pharmaceutically acceptable excipient.

The present invention also relates to the use of a compound of formula I as defined above for the preparation of a medicament for treating a disease or condition involving treatment by matrix metalloprotease inhibition and more specifically a disease or condition comprising treatment by inhibiting matrix metalloprotease type 13 (MMP-13) such as arthritis. rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), macular degeneration and some types of cancer (ARMD).

The present invention also relates to a method of treating a disease associated with an MMP imbalance and more specifically

01-1699-03 -C

MMP-13, wherein said method comprises the step of administering to a patient in need of such treatment a pharmaceutically effective amount of an MMP inhibitor compound of the present invention or a pharmaceutical composition comprising the compound.

Among the various diseases associated with MMP imbalances, the compound of formula I inhibiting MMP13 of the present invention is particularly useful in the treatment of all diseases caused by degradation of extracellular matrix tissue and more specifically in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), age-related macular degeneration (ARMD), and cancer.

In a most preferred embodiment, the compound of formula I as defined herein will be used preferably for the treatment of arthritis, osteoarthritis and rheumatoid arthritis.

The compounds of the present invention are administered in the form of compositions that are suitable for the nature and severity of the disease being treated. The daily dose in a human will be between 2 mg and 1 g of the compound, which can be concentrated in one or more doses. The composition is prepared by procedures well known to those skilled in the art and typically comprise 0.5 to 60% by weight of the active ingredient (compounds of Formula I) and 40 to 99.5% by weight of a pharmaceutically acceptable vehicle.

Thus, the compositions of the present invention are prepared in forms that are compatible with the desired method

01-1699-03-Ce administration. For example, the following pharmaceutical forms are contemplated, but the invention is not limited to the following examples:

1) Forms for oral administration

Drinking solutions, suspensions, sachets containing powder for drinking solutions, sachets containing powder for drinking suspensions, gastro-resistant gel capsules, prolonged-release forms, emulsions, HPMR 'capsules or gel capsules, lyophilizates intended to dissolve under lysyme .

2) Forms for parenteral administration

Intravenous route:

Aqueous solutions, water / cosolvent solutions, solutions employing one or more solubilizing agents, colloidal suspensions, emulsions, nanoparticle suspensions that can be used for sustained release injectable forms, dispersed forms and liposomes.

Subcutaneous / intramus-ciliary route:

In addition to the forms which can be used intravenously and which can also be used for the subcutaneous and intramuscular routes, other suitable forms of suspension, dispersed forms, sustained release gels and sustained release implants.

3) Forms for topical administration

The most common topical forms that can be distinguished are creams, gels (aqueous phases gelled with polymers), patches that are impregnated and intended for direct adherence to

01-1699-03-Che and may be used in the treatment of cermatosis without percutaneous penetration of the active substance, sprays, emulsions and solutions ·

4) Forms for pulmonary administration

This category includes forms such as aerosol solutions, powders for inhalers, and other suitable forms.

5) Molds for nasal use

This category includes in particular drop solutions.

6) Forms for rectal administration

Suppositories and gels can be mentioned here.

It is also contemplated to use forms which allow the administration of ophthalmic solutions or allow the vaginal administration of the active ingredient.

Another important category of pharmaceutical forms that can be used in the context of the present invention are the forms which improve the solubility of the active ingredient. For example, it is contemplated to use aqueous solutions of cyclodextrin and, more particularly, forms containing hydroxypropyl-β-cyclodextrin. A detailed review of this type of pharmaceutical form is given in an article published in the Journal of Pharmaceutical Sciences, 85 (11),

1142-1169 (1996), and this article is incorporated herein by reference.

The various pharmaceutical forms recommended above are described in detail in the book "Pharmacie galénique by A. Lehir (ed.

Masson, 1992 (sixth edition)), and this book is incorporated herein by reference.

01-1699-03 -C

INTERMEDIATE

The present invention also relates to intermediates of formula III

σπ) where R ³ has the same meaning as given above for the compound of the formula I.

In another aspect, the present invention also relates to an intermediate of formula IV:

wherein R ¹ and R ³ have the same meanings as given above for compounds of formula I.

METHODS OF SYNTHESIS OF THE GENERAL FORMULA COMPOUNDS

According to the present invention, the abbreviations have the following meanings:

DEAD: Diethyl azodicarboxylate

DIPEA: N, N-diisopropylethylamine

DMF: N, N-dimethylformamide

01-1699-03-CE

NMP: 1-methyl-2-pyrrolidinone

TF: tetrahydrofuran

TOTU: O - [(ethoxycarbonyl) cyanomethyleneamino] -N, N, N, N'-tetraraethyluronium tetrafluoroborate

EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HOBT: 1-hydroxybenzotriazole hydrate

The compounds of the present invention can be obtained by several synthetic procedures. Some of the appropriate synthetic procedures are described below:

A) General method:

The general process for the synthesis of compounds of formula I is described in the following scheme.

(Note: for better clarity, subscripts are retained in the formulas in the following schemes as shown in the English original.)

01-1β99-03-Ωε

wherein R ⁷ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl or heteroaryl, R is C 1 -C 6 alkyl, aryl , arylalkyl having 1 to 6 carbon atoms in the alkyl moiety, an aromatic or non-aromatic heterocycle, or a cycloalkyl

01-1699-03-Ce group, and R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , A, W, Y, Z ¹ have the same meanings as above for the compound of the general formula I.

B) Synthesis method number 1

Compounds first using the present method of Scheme 1 of the invention:

can be obtained

Scheme 1:

Method A

wherein each substituent is as defined for a compound of Formula I.

The intermediate of formula II, which is the starting material for the synthesis process illustrated in Scheme 1 above, can be prepared according to the following Scheme 2 below:

01-1699-03 -C

Scheme 2:

The intermediate of formula (II), which is a starting material in the process for the synthesis of compounds of formula (I) of the present invention illustrated in Scheme 1 above, can also be prepared according to the procedure illustrated in Scheme 3 below.

Scheme 3:

Compound (III) in accordance with the method described in Scheme (II) according to the synthetic formula below:

can be prepared 1 above from the compound of Scheme 4 (Method A)

Scheme 4 / Method A

is as defined above for the compound of formula I.

1-1699-03-Ce

In another aspect, an intermediate of Formula III ', in accordance with the synthetic route illustrated in Scheme 1 above, can be prepared according to Method B, which is illustrated in Synthetic Scheme 5 below:

Scheme 5:

wherein R ³ is as defined for a compound of formula (I).

In another aspect, an intermediate of formula III wherein R ³ is benzyl may be obtained in accordance with the synthetic route illustrated in Scheme 1 above, according to Method C illustrated in Synthetic Scheme 6 below:

Scheme β / Method C:

benzyl isocyanate

The present invention provides a process for the preparation of a compound of formula I:

finally also

01-1699-03 -C

wherein R ¹ , R ² , R ³ , Z ¹ , A, n and m are defined in the description of the invention, X ¹ , X ² and X ³ are CH, Y is O, Z is NR ⁷ and W is O, wherein said process is characterized by comprising reacting a compound of formula II:

(Π) with pyridine and a compound of formula V:

O = C = NR (V) wherein R ³ is as defined in the disclosure, to give a compound of formula VI:

where R ³ is as defined above, (VI)

01-1699-93-Ce followed by a reaction in the presence of a hydroxide of formula III, wherein the compound of formula VI is lithium to yield compound p

R is as defined in the description of the invention.

(ΙΠ) is also characterized by the compound

R ³ is as defined in formula I, reacted in the presence of TOTU, with a compound of general formula

The above process is of the formula III, wherein for a compound of the general acid activator such as formula VII:

(VH) wherein R ^; is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , man are as defined above for compounds of Formula I to give a compound of Formula I wherein R ¹ is hydrogen, X 1, X ² and X ³ are CH, Y is O, Z is NR ⁷ , W is an oxygen atom, and A, R ² , R 0, Z ³ , and m are as defined above.

The present invention also relates to a process for the preparation of a compound of formula I wherein R ¹ , R ² , R ³ , A, Z, m and n are

01-1699-03-Ce defined for a compound of formula I, X ¹ , X ² and X ³ are CH, W is O, Y is O and Z is NR ⁷ , wherein said method is characterized in that: a compound of formula VI:

(VI) wherein R ³ is as defined in the description, reacts in the presence of a base with a compound of formula XR ¹ , wherein R ¹ is as defined in the description of the invention and X is a leaving group such as a halogen atom,

wherein R ³ and R ¹ are as defined above.

The above process is also characterized in that the compound of formula IX:

01-1699-03 -C

the compounds wherein R ¹ and R ³ are as defined above.

The above process is also characterized in that:

compound

(IV) wherein R ³ is as defined for Formula I, reacts in the presence of an acid activator such as a compound of Formula VII:

compound

TOTU, Sat (R ¹ )

A)

R f

.NH

CVN)

Wherein R ⁷ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are as defined in the description of the invention, to obtain a compound of formula I:

wherein R ¹ , R ² , R ³ , A, Z ¹ , m and n are as defined herein, X ¹ , X ² and X ³ are CH, W is O, Y is O, and Z is NR ⁷ .

Another object of the present invention is a process for the preparation of a compound of formula I wherein R ¹ , R ² , R ³ , W, X ¹ , X ² , X ³ , A, Z ¹ , m and n are as defined for the compound of formula I, Y is NR ⁷ , wherein R ¹ is hydrogen, oxygen and Z is a compound of formula I;

reacts in the presence of a base with a compound of formula XR ¹ , wherein R ¹ is as defined in the description of the invention and X is a leaving group, such as a halogen atom, to yield

01-1699-03-Ce of a compound of formula I, wherein R ¹ is as defined in the disclosure.

C) Synthesis method No. 2

The compounds of the present invention can also be prepared by the method outlined in Scheme 7 below.

Scheme 7:

(VO) (XIV) P) in which all the general substituents are as defined for the compounds of the general formula I.

The present invention also relates to a process for the preparation of a compound of formula I wherein X, X and X are CH, W is O, Y is O, Z is NR ⁷ , R ¹ , R ³ , A, R ² , Z ¹ , m and n are the same as defined for the compound of the formula I, characterized in that the compound of the formula

MeO (xi)

Wherein R ¹ is as defined above, reacts with aluminum chloride in a solvent such as benzene to give a compound of formula XII:

(ΧΠ) where R ¹ is as defined above.

The process for preparing the compound of formula I above is also characterized in that it comprises the step of reacting the compound of formula XII in the presence of lithium hydroxide and dioxane / water to give a compound of formula XIII:

(ΧΓΠ) where R ¹ is as defined above.

A process for preparing a compound of the formula characterized in that the formula comprises the step of reacting XIII in the presence

I is also an acid activator compound such as TOTU with a compound of formula VII:

(V H)

01 When

5-0362 wherein R '' is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms in each alkyl moiety, cycloalkyl, aryl and heteroaryl, and A R ² , Z ¹ , m and n are defined in the description of the invention to give a compound of formula XIV, wherein X ¹ , X ² and X ³ are CH, W is O, Y is O, and R ⁷ , R ¹ .

A, R ² , Z ¹ , and m are as defined above:

(XIV)

The process for preparing a compound of formula I above is also characterized in that it comprises the step of reacting a compound of formula XIV with a compound XV of formula XR ³ wherein R ³ is as defined in the invention and X is a leaving group such as a halogen atom. to obtain a compound of formula I wherein X ¹ , X ² and X ³ are CH, W is oxygen, Y is oxygen, Z is NR ⁷ , and R ⁷ , R ¹ , A, R ² , Z ¹ , m and n are the same as defined for the compounds of formula I.

D) Preparation Method 3

The compounds of formula I of the present invention can also be prepared by the method outlined in Scheme 8 below:

01-1699-03-CE

Scheme 8:

ω

In this scheme, each general substituent is the same as defined for the compound of formula I above.

Accordingly, the present invention also relates to a process for the preparation of a compound of formula I as defined above, wherein X ¹ , X ² and X ³ are CH, W is O, Y is O and Z is O, which is characterized in that that the compound of formula III:

01-1699-03 -C

(ΙΠ) where R ³ is the same of formula I as defined for the compound reacts with a compound of formula XVI:

(XVI) wherein A, R ² , Z ¹ , and the compound of general formula to give compound n are the same as of formula I of general formula XVII:

defined for

(XVTI) where A, in the description of oxygen

R ² , R ³ , Z ', man of the invention, X ¹ , X ² and are as defined above X ³ are CH, and W is an atom

According to a process for preparing a compound of formula I above, said process also comprises the step of reacting a compound of formula XVII in the presence of a base with a compound of formula XR ¹ wherein R ¹ is as defined in the description and X is a leaving group. such as

01-1699-03-C halo, to give a compound of formula I wherein X ¹ , X ² and X ³ are CH, W is O, Y is O, Z is O, and A, R ² R ³ , R ¹ , Z ¹ , m and n are the same as defined in the description of the invention.

The present invention also relates to a process for the preparation of a compound of formula I as defined above, comprising the step of reacting a compound of formula IV with a compound of formula XVI to obtain a compound of formula I wherein X ¹ , X ² and X ³ is CH, W is O, Y is O and Z is O.

E) Preparation Method 4

The compounds of the present invention, and in particular the compounds of the present invention that form pyridine esters, can be obtained by the procedure illustrated in Scheme 9 below:

Scheme 9:

CHCI,

TEA

KMnO,

Η, Ο

NMP

YOUR »

H

Qoo)

wherein all the general substituents of the intermediates have the same meanings as given for the compounds of formula I as defined in the description of the invention.

Q1-1699-O3-CE

Accordingly, the present invention also provides a process 23 for the preparation of a compound of formula I wherein X and X are CH, X ¹ is nitrogen, Z is oxygen and Y is oxygen, which comprises the step of: wherein the compound of formula XIX:

(XIX) is reacted with pyridine and compound V of formula O = C = NR ³ , wherein R ³ is as defined for compounds of formula I to form a compound of formula XX:

(XX) wherein R ³ is as defined above.

The process for preparing a compound of formula I above is also characterized in that it comprises the step of reacting a compound of formula XX in the presence of potassium permanganate to give a compound of formula XXI:

(XXI)

Wherein R ³ is as defined above.

The above method wherein the compound in the presence of SOCl ₂ and formula XXII:

is also characterized in that it comprises a step of reacting formula XXI with chloroform to obtain a compound

(XXH) wherein R ³ is as defined above.

A process for the preparation of a compound of formula I according to the present invention is also characterized in that it comprises the step of reacting a compound of formula XXII with a compound of formula XVI:

(R ¹ ) (XVI) wherein A, R ² , Z ¹ , m and n are as defined for compounds of formula I to give a compound of formula XXIV, wherein X ² and X ³ are CH and A, n, m, Z ¹ , R ² and R ³ are as defined in the description of the invention.

ABOUT

ABOUT

01-1699-03-CE

The compounds of the present invention that form pyridinamide can also be obtained by the method illustrated in Scheme 10 below.

Scheme 10:

CHjCLj

N-iodosuccinimide ¹

sorting (AcO) j

Cul

KjCOj

DMF and Ci

Ni

AlCl _and 1 Benzéir

- No.

^ NHR, this one

T PTPPA

DIPEA ABOUT DMF

ND.

totu

DIPEA

DMF

Accordingly, the present invention also provides a process for the preparation of a compound of formula I wherein X and X are CH, X is N, Z is -NR ⁷ wherein R ⁷ is as defined for compounds of formula I, W is an oxygen atom and Y is an oxygen atom, wherein the method is characterized in that it comprises a step wherein the compound of formula XXV:

(XXV)

01-1599-03-Ce is reacted in a first step with N, N'-dimethylformamide dimethylacetal boiling in dimethylformamide and in a second step reacted with N-iodosuccinimide to obtain a compound of formula XXVI:

followed by reaction of a compound of formula XXVI with ethyl acrylate in the presence of palladium diacetate, copper (I) iodide and a base to give a compound of formula XXVII:

followed by reaction of a compound of formula XXVII in the presence of lithium hydroxide to give a compound of formula XXVIII:

and named

compound of formula XXVIII:

(ΧΧΥΙΠ) either reacts in the presence of an acid activator such as TOTU with a compound of formula VII:

01-1699-03-Jul (VII)

wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to obtain a compound of formula XXIX:

my

(XXIX) wherein A, R ² , R ⁷ , Z ¹ , m and n are as defined above, and X ² and X ³ are each -CH, or reacted in the first step with aluminum chloride in the presence of benzene and in the second step in the presence of an acid activator , such as TOTU, with a compound of formula VII:

(VH) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to give a compound of formula XXX:

01-1699-03 -C

Me

(XXX) wherein A, R ² , R ⁷ , Z ¹ , m and n are as defined above and X ² and X ³ are each -CH, followed by reaction of a compound of formula XXX with a compound of formula R ³ -X, wherein R ³ is as defined for a compound of Formula I in the presence of a base to give a compound of Formula XXXI:

The compounds of the present invention which form pyridinamide, and in particular pyrido [3,4-d] pyrimidine derivatives, can also be obtained by the method illustrated in Scheme 11 below:

01-1699-03 -C

Accordingly, the present invention also provides a process for the preparation of a compound of formula I wherein X ¹ and X ³ are CH, X ² is nitrogen, Z is -NR ⁷ , wherein R ⁷ is as defined for the compound of formula I, W is oxygen and Y is an oxygen atom, wherein the method is characterized in that it comprises the step wherein the compound of formula XXXII:

reacts in the activator of the first acid step, v with selenium dioxide in the presence of the second step with dimethylhydrazine, and

01-1699-03-Ce of the third step with N, N'-dimethylformamide dimethyl acetal boiling in dimethylformamide, to give the compound of formula XXXIII:

(ΧΧΧ3Π) followed by reaction of a compound of formula XXXIII with methyl acrylate in the presence of palladium diacetate to give a compound of formula XXXIV:

followed by reaction of the compounds with acetic acid to obtain the ny formula of the compound

XXXIV with chlorobenzene of formula XXXV:

followed by reaction of a compound of formula XXXV in the presence of a base to give a compound of formula XXXVI:

01-1699-03 -C

4 (XXXVI)

said compound of formula XXXVI either reacts in the presence of an acid activator such as TOTU with a compound of formula VII:

(VH) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to give a compound of formula XXXVII:

-CH, or reacting, in a first step, with aluminum chloride in the presence of benzene and in a second step in the presence of an acid activator such as TOTU, with a compound of formula VII:

03-01-169S -C

(VH) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to give a compound of formula XXXVIII:

(XXXVIII) wherein A, R ² , R ⁷ , -CH,

Z ¹ , m and n are as defined above and X ¹ and X ³ are each followed by reaction of a compound of formula XXXVIII with a compound of formula R ³ -X, wherein R ³ is as defined for compounds of formula I in the presence of a base, to obtain a compound of formula XXXIX:

(XXXIX)

The present invention is further illustrated by examples, which in no way limit its scope.

01-1699-03 -C

DETAILED DESCRIPTION OF THE INVENTION

Preparation A: dimethyl 4-aminoisophthalate

Preparation according to Scheme 2

Step 1-2: 4-nitroisophthalic acid

To a suspension of 25 g (138 mmol) of 5-methyl-2-nitrobenzoic acid in 300 mL of water was added 5 g (89.1 mmol) of KOH. The mixture is heated to 90 ° C and 158 g of KMnO ₄ (414 mmol) are added in portions while rinsing with water. After 3 hours, the reaction mixture is filtered through diatomaceous earth and the filtrate is acidified to pH = 1 with concentrated HCl. The precipitate obtained is collected by filtration and dried under vacuum to give 15.3 g of product; yield = 53%.

NMR: DMSO δ (ppm) δ, 62-5.70 (d, 1H); 7.88 (d, 1H); 8.16 (s, 1 H).

Step 2-2: Dimethyl 4-nitroisophthalate

A mixture of 12.75 g (60.4 mmol) of 4-nitroisophthalic acid from the previous step and 13 ml of H ₂ SO ₄ and 100 ml of methanol is heated to boiling overnight. After cooling, the methanol is removed in vacuo, the residue is dissolved in 400 ml EtOAc and the organic phase is washed with 50 ml H ₂ O and then 50 ml 5% NaHCO 3 solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a crystalline residue. 12.17 g. Yield 84%.

NMR DMSO ^{Χ Η δ} (ppm) 3.86 (s, 3H); 3.91 (s, 3H); 8.16 (d, 1H);

8.29-8.34 (m, 2 H).

Step 3-2: Dimethyl 4-aminoisophthalate

The compound of the previous step is reduced with hydrogen in the presence of palladium catalyst. Filtration through

01-1699-03-Celite and concentration gave 5.12 g of product, yield = 70%, mp 127-128 ° C.

NMR CDC1 ₃ ^x H δ (ppm) 3.87 (s, 3H); 3.88 (s, 3H); 6.30 (bs, 2H);

6.65 (d, IH); 7.89 (dd, 1H); 8.57 (d, IH).

Preparation of Scheme 3 - J. Org, Chem. 1997, 62 (12), 40884096

Step 1-3: dimethyl 4-amino-1-hydroxycyclohexa-3,5-diene-1 *, 3-dicarboxylate

A 1 liter three-necked flask equipped with a reflux condenser was charged with 526 ml of benzene and 250 ml of methyl acrylate. The mixture was placed under an inert atmosphere without humidity and 10 g (70.8 mmol) of methyl 5-amino-2-furancarboxylate was added. The mixture was heated to boiling for 24 h. It is then concentrated to dryness on a rotary evaporator at 50 ° C and a vacuum of 20 mm Hg. The residue is purified by chromatography on silica gel in dichloromethane progressively enriched with ethyl acetate. 15 g of a yellow precipitate are obtained, yield = 93%. TLC: CH ₂ Cl ₂ / EtOAc 70:30 (by volume) R f = 0.35; mp = 101.3 ° C.

NMR CDC1 ₃ ^X H δ (ppm) 2.87 (d, 1H); 2.93 (d, 1H); 3.20 (s, 1H);

3.71 (s, 3H); 3.82 (s, 3H); 6.02 (d, IH); 5.60-6.40 (bs, 2H); 6.17 (d, 1H).

Step 2-3: dimethyl 4-aminoisophthalate

To a 1 L three-necked flask equipped with a reflux condenser was charged 15 g (66 mmol) of the compound obtained in steps 1-3 and 600 mL of benzene. The mixture is placed under an inert atmosphere protected from moisture and 13.8 g (12 ml, 98 mmol) of BE ₃ etherate are added with stirring. The mixture was heated to boiling for 2 min and then cooled to room temperature. Saturated aqueous was added

Sodium bicarbonate solution (pH 9), the phases are separated, the aqueous phase is extracted twice with dichloromethane. The organic phases are combined and dried over Na ₂ SO ₄ . After removal of the solvent in vacuo, 13.8 g of residue are purified by chromatography on silica gel in dichloromethane. 8.5 g of crystalline product are obtained, yield = 62%. TLC: CH ₂ C1 _2, Rf = 0.30; mp = 130.1 ° C.

NMR: CDCl ₃ ^: H δ (ppm) 3.87 (s, 3H); 3.88 (s, 3H); 6.30 (bs, 2H);

6.65 (d, IH); 7.89 (dd, 1H); 8.57 (d, IH).

Preparation B: 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

Preparation according to Scheme 4

Step 1-4: methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

4 g (19.1 mmol) of the compound of Preparation A and 40 ml of pyridine are charged to a 50 ml reflux condenser with moisture protection and 3.2 g (24 mmol) of benzyl isocyanate are added. The colorless solution was stirred and heated to 95-100 ° C. After 6 hours, 1 ml of benzyl isocyanate was added and stirring was then continued at 100 ° C overnight. The next day, the reaction mixture was cooled and poured into 400 mL of ice / water and allowed to stir for 30 minutes. The precipitate obtained is then collected by filtration and the product is suspended under boiling in 150 ml of ethanol. After cooling, the product was collected by filtration to give 3.7 g of the product, yield = 62%.

NMR: DMSO ^2? (Ppm): 3.75 (s, 3H); 4.95 (s, 2 H); 7.1-7.2 (m;

6H); 8.05 (d, IH); 8.35 (s, 1H); 11.8 (bs, 1H).

Step 2-4: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

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1.5 g (4.84 mmol) of methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate, 14 ml of dioxane and 48 ml of ethanol are added to a 100-round reflux flask. ml of water. 0.41 g (9.68 mmol) of hydrated lithium hydroxide is then added with stirring. The mixture was heated to boiling for 1 hour (dissolution). After cooling in an ice bath, the mixture was acidified to pH 1 with concentrated hydrochloric acid. The fine precipitate was collected by filtration to give 1.3 g of product; yield = 96%.

NMR: ^{DMSO; H} δ (ppm): 5.1 (s, 2H); 7.2-7.35 (m, 6H); 8.15 (d, 1H); 8.48 (s, 1H); 11.85 (s, 1H); 13.1 (bs, 1H).

Preparation according to scheme 5

Step 1-5: Dimethyl 4- (3-benzylureido) phthalate

To a 1 L reflux and round-bottom flask was added 10 g (48 mmol) of the compound of Preparation A, 200 mL of anhydrous toluene, 100 mg of activated carbon, and then 12 g (40 mmol) of triphosgene. The suspension is stirred and heated to boiling for 2 h, then filtered through diatomaceous earth and then concentrated to dryness at 50 ° C and 20 mm Hg vacuum. The residue was dissolved in 200 ml of anhydrous toluene and 4.7 ml (43 mmol) of benzylamine was added over a few minutes with stirring. A precipitate formed immediately, toluene (200 ml) was added and the mixture was stirred at room temperature overnight. The next day the precipitate was collected by filtration and washed thoroughly with toluene and then with ether. Drying in vacuo afforded 13.9 g of product; yield = 84.6%. TLC: CH ₂ Cl ₂ / acetone 98: 2 Rf = 0.35; mp = 181.9 ° C.

NMR: ^{DMSO; H} δ (ppm) 3.8 (s, 3H); 3.9 (s, 3H); 4.3 (s. 2H); 7.2-7.4 (m, 5H); 8.0 (d, 1 H); 8.3 (s, 1H); 8.5 (s, 1H); 8.55 (d, 1H); 10.2 (s, 1 H).

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Step 2-5: methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

A 1 L reflux condenser with moisture protection was charged with 13.7 g (40 mmol) of the compound obtained in Step 1-5, 300 mL of methanol and then 1.3 g (24 mmol) of sodium methoxide. The white suspension was heated to boiling for 3 h, half of the methanol was then removed on an evaporator at 50 ° C. The mixture was cooled and acidified to pH 4 with 2 ml of concentrated hydrochloric acid and then stirred for 15 min. The crystalline product is then collected by filtration to give 12 g of product; yield = 96.7%; TLC: CH ₂ Cl ₂ / acetone 98: 2 Rf = 0.05-0.2;

mp = 248.1 ° C.

^X H NMR DMSO δ (ppm) 3.9 (s, 3H); 5.1 (s. 2H); 7.2-7.4 (m. 6H);

8.15 (d, IH); 8.45 (s, 1H); 11.9 (bs, 1H).

Step 3-5: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product is obtained in an analogous manner to that described in Step 2-4 of Preparation B using the compound obtained in the previous Step 2-5.

Preparation according to scheme 6:

Step 1-6: 3-Benzyl-6-bromo-ΙΗ-quinazoline-2,4-dione

To a 250 ml reflux condenser and moisture protection flask was charged 10 g (46.3 mmol) of 2-amino-5-bromobenzoic acid, 100 mL of anhydrous pyridine and 6.16 g (46.3 mmol) of benzyl isocyanate. The solution was heated to boiling for 36 h and stirred. The reaction mixture was cooled and water was added to start precipitation. The mixture was allowed to crystallize for 1 h and then the precipitate was collected

01-1699-03-Ce was collected by filtration and washed. The crude product (8 g) was purified by crystallization from boiling ethanol to give 3.4 g of the product.

NMR ^DMSO: Η δ (ppm): 4.9 (s, 2H); 7.0 (d, 1H); 7.03-7.2 (m, 5H);

7.65 (d, 1H); 7.85 (s, 1H); 11.5 (s, 1H).

Step 2-6: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile

2.5 g (7.5 mmol) of the compound of Step 1-6 are charged to a 50 mL reflux condenser with moisture protection. 1.215 g (13.6 mmol) of copper cyanide and 22.5 ml of 1-methyl-2-pyrrolidinone. The beige solution was heated to an internal temperature of 200 ° C for 1.5 h. The reaction mixture is concentrated to dryness at 80 ° C under vacuum <1 mm Hg. The residue was dissolved in 300 mL of 2N NH ₄ OH and extracted 3 times with dichloromethane. The insoluble material was treated twice with 20 ml of 50:50 (by volume) to MeOH / CH ₂ Cl _2nd The organic phases are combined and washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. Crystallization from 10 ml of CH ₂ C1 ₂ to give 1.2 g of black product; yield 60%. TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50

NMR DMSO * δ (ppm): 4.82 (s, 2H); 6.97-7.12 (m, 6H); 7.80 (d, 1H); 8.1 (s, 1H); 11.75 (bs, 1H).

Step 3-6: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

1.4 g (5.05 mmol) of the compound of Step 2-6 and 35 mL of water were charged to a 100 mL reflux condenser flask and then carefully added 35 mL of H ₂ SO ₄ . The suspension is heated to boiling for 3 h, after cooling the beige precipitate is collected by filtration and washed neutral with water and then with methanol. 1.5 g of product are obtained, yield = 100

0.10; mp = 360 ° C.

%. TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf

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Preparation C: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

Step 1: methyl 3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

In a 250 ml three-necked flask was charged 11.8 g (38.0 mmol) of the product of Preparation B, 120 ml of dimethylformamide and 7.6 g (57 mmol) of K 2 CO 3. The suspension was stirred at room temperature for 15 min. Then 27 g (12 mL, 190 mmol) of iodomethane are added over 2 min. The suspension is stirred at room temperature for 30 to 45 minutes. The solvent was removed in vacuo and the residue was dissolved in 500 mL of dichloromethane and washed with 3x 300 mL of water. The organic phase is dried and the solvent is removed. 12 g of product are obtained; yield = 97.4%. TLC: CH ₂ Cl 2 / acetone 98: 2 Rf = 0.60; mp 179.3 ° C.

NMR DMSO δ (ppm) 3.6 (s, 3H); 3.90 (s, 3H); 5.1 (s. 2H); 7.27.4 (m, 5H); 7.55 (d, IH); 8.25 (d, IH); 8.6 (s, 1H).

Step 2: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product was obtained in 100% yield (10 g) by a procedure analogous to that of Step 2-4 of Preparation B using 9.5 g (29.3 mmol) of the compound obtained in Step 1. TLC: CH ₂ Cl ₂ / MeOH 90:10 Rf = 0.50; mp 227.2 ° C.

DMSO ‘H δ (ppm) 3.55 (s, 3H); 5.15 (s. 2H); 7.2-7.4 (m, 5H); 7.55 (d, 1H); 8.25 (d, IH); 8.6 (s, 1 H); Δ 3.2 (bs, 1H).

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Preparation D: 1-methyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

Step 1: methyl 3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

A round flask was charged with 5.5 g (26.3 mmol) of the compound of Preparation A and 50 mL of pyridine. Then 5.0 g (33.1 mmol) of 3-fluorobenzyl isocyanate is added. The mixture was heated to reflux for 6 hours and then 0.8 g (5.3 mmol) of 3-fluorobenzyl isocyanate was added in one portion. Heat the mixture to boiling overnight. The mixture was cooled and the product was precipitated by the addition of water and filtered. The product is suspended in hot ethanol and filtered to give 6.7 g of the desired compound (yield 78%).

Mass spectrum: m / z (APCI, AP +) 329.1 [M] &lt; ^{+ &gt};.

CHN analysis - calculated (%): C 62.20; H, 3.99; N, 8.53; Found (%): C 62.09; H, 3.85; N, 8.42.

Step 2: methyl 1-methyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

To a solution of 1.8 g (5.5 mmol) of the product from Step 1 above was dissolved in 30 mL of dimethylformamide and 1.8 g (8.1 mmol) of cesium carbonate was added. The mixture was stirred for 10 min and then iodomethane (1.1 g, 8.1 mmol) was added. Stirring is continued overnight at room temperature. Water (60 ml) was then added and the product was extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined and washed with saturated aqueous sodium chloride solution (4 x 20 mL) and dried over MgSO ₄ . The solid product was suspended in hot ethyl acetate and filtered to give 1.7 g (90% yield) of the title compound; mass spectrum: m / z (APCI, AP +) 343.1 [M] ⁺ .

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CHN analysis: calculated (%): C 63.15; H, 4.42; N, 8.18; Found (%): C, 63.02; H, 4.26; N, 8.06.

Step 3: i-methyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product (0.71 g; yield 76%) was obtained in a manner analogous to that of Step 2-4 of Preparation B using the compound obtained in the previous Step 2; mass spectrum: m / z (APCI, AP +) 329.0 [M] ⁺ .

CHN analysis: calculated (%): C, 62.20; H, 3.99; N, 8.53; found C 61.94; H, 3.78; N, 8.57.

Preparation E: 1-ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

Step 1: methyl 1-ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

To a solution of 2.0 g (6.1 mmol) of the compound of Step 1 of Preparation D in 30 mL of dimethylformamide was added 1.96 g (9.2 mmol) of cesium carbonate. The mixture was stirred for 10 minutes and then 1.4 g (9.2 mmol) of iodoethane was added. Stirring is continued overnight at room temperature. Water (60 ml) was then added and the product was extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined and washed with saturated aqueous sodium chloride solution (4 x 20 mL) and dried with ethyl acetate.

MgSO ₄ . The solid product is suspended in hot and filtered to give 1.4 g (yield: 67%) of the title compound; mass spectrum: m / z (APCI, AP +) 357.1 [M] &lt; ^{+ &gt};.

CHN analysis: calculated (%): C 64.04; H, 4.81; N, 7.86; Found (%): C, 63.72; H, 4.68; N, 7.75.

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Step 2: 1-Ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound (1.1 g; yield 71%) was obtained according to the procedure of step 2-4 of preparation B using the compound obtained in previous step 1; mass spectrum m / z (APCI, AP +) 343.0 [M] ⁺ .

CHN analysis: calculated (%): C 63.16; H, 4.42; N, 8.18; Found (%): C, 63.06; H, 4.41; N, 8.03.

Examples 1 to 461 illustrate (without limitation) the synthesis of compounds of formula (1) that are particularly active according to the present invention.

Example 1

3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide

0.150 g (0.5 mmol) of the compound of Preparation B and 8.0 ml of anhydrous dimethylformamide were added to a 25 ml moisture-protected round flask with stirring. Then 0.054 g (56 μΐ, 0.51 mmol) of benzylamine and 0.17 g (0.51 mmol) of TOTU are added. The solution was cooled to 0 ° C in an ice bath and then 0.132 g (0.18 mL, 1.02 mmol) of N, N-diisopropylethylamine was added. The mixture was allowed to reach room temperature overnight. After TLC analysis (90:10 CH ₂ Cl ₂ / MeOH), dimethylformamide was removed in vacuo. The crystalline residue obtained is taken up in dichloromethane with the addition of methanol (only for complete dissolution). The organic phase is washed

01-1699-03-Eng ml of 1N HCl, 40 ml of water, 40 ml of saturated aqueous sodium bicarbonate solution and finally 40 ml of water. The organic phase is dried over Na ₂ SO ₄ and the solvents are removed in vacuo. 0.140 g of product is obtained, which is recrystallized from 30 ml of acetonitrile: 0.110 g of product is obtained; yield 56%; TLC:

CH ₂ Cl ₂ / MeOH 90:10 R f = 0.65.

NMR DMSO ^: H? (Ppm): 4.45 (d, 2H); 5.1 (s. 2H); 7.1-7.4 (m, 11H);

8.1 (d, IH); 8.5 (s, 1H); 9.15 (m, IH); 11.15 (bs, 1H).

IR: 3425, 2364, 1722, 1640, 1509, 1442, 1304, 1261,

1078, 927, 845 cm ^-1 ;

mp = 241.2 ° C; HPLC: 98.3%.

Example 2 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-pyridylmethyl) amide

The product was obtained in a yield of 46% (0.090 g) according to the procedure of Example 1 using 4-picolylamine and after recrystallization from 50:50 EtOAc / EtOH. TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

NMR DMSO ¹ H δ (ppm): 4.5 (d, 2H); 5.1 (s. 2H); 7.2-7.4 (m. 8H);

8.15 (d, 1H); 8.5 (d. 2H); 8.55 (s, 1H); 9.25 (t, 1H); 11.75 (s, 1 H).

IR: 3250, 1725, 1669, 1642, 1623, 1450, 1345, 1301,

1075, 1006, 830 cm ^-1 ;

01-1699-03-Ce mp = 305.2 ° C; HPLC: 95.1%.

Example 3

3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide

O O

The product was obtained in a yield of 64% (0.140 g) according to the procedure of Example 1 using piperonylamine and crystallization from acetonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.65.

^X H NMR DMSO δ (ppm): 4.35 (D, 2H); 5.1 (S, 2H); 5, 95 (S, 2H); 6,7- 6.95 (m, 3H); 7.15-7.4 (m 6H); 8.15 (D, lH); 8.5 (S, lH); 9.1 (T, 1H); 11.7 (bs, 1H). IR spectrum: 3200, 1727, 1636 1493 1444, 1299 1261 1041 938, 841, 763, 726 cm ^-1 ; mp = 256 ° C; HPLC: 99%.

Example 4 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-thienylmethyl) amide

The product was obtained in a yield of 40% (0.080 g) according to the procedure of Example 1 but using 2-thienylmethylamine and after crystallization from acetonitrile.

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TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.65; NMR DMSO ³ Η δ (ppm): 4.35 (d, 2H); 4.85 (s, 2 H); 6.7-6.85 (m. 2H); 6.95-7.2 (m, 7H); 7.9 (d, 1H); 8.3 (s, 1H); 9.05 (t, 1H); 11.55 (bs, 1H).

IR: 1729, 1637, 1511, 1444, 1346, 1298, 1261, 1072,

845.763 cm ^-1 ;

mp = 236.3 ° C; HPLC: 98.7%.

Example 5 3-Benzyl-2,4-dioxo-1,2,3,4-trahydroquinazoline-6-carboxylic acid (3-pyridylmethyl) amide

The product was obtained in a yield of 66% (0.130 g) according to the procedure of Example 1 but using 3- (aminomethyl) pyridine and crystallization from acetonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.40.

NMR : DMSO ^{Χ Η} δ (ppm) : 4,5 (D 2 H); 7.7 (D, 1H); 8, 15 (D, 1H) ; 8.45 (T, 1H); 11.8 (S, 1H). Company ID MS: 3345. 1716 1670

5.15 (s. 2H); 7.15-7.4 (m. 7H);

(D, lH); 8.55 (d, 2 H); 9.25

1638 1621 1450 1433 1348

1298, 1068, 829, 774 cm ^-1 ;

mp = 252.3 ° C, HPLC:

Example 6

97.4%.

3-Benzyl-2,4-dioxo-1,2,3,4-tetraltydoquinazoline-6-carboxylic acid 4-methoxybenzylamide

The product is obtained in a yield of 47.2% (0.100 g) according to the procedure of Example 1 but using 4-methoxybenzylamine and after blood-crystallization from acetonitrile.

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TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.45.

NMR: ^{DMSO; H?} (Ppm): 3.7 (s, 3H); 4.4 (d, 2 H); 5.1 (s. 2H); Δ, (d, 2H); 7.2-7.4 (m. 8H); 8.15 (d, IH); 8.5 (s, 1H); 9.15 (t, 1H)

11.8 (bs, 1H).

IR: 3400, 3210, 1727, 1638, 1513, 1441, 1300, 1253

1173, 1040, 843, 760 cm ^-1 ;

mp = 269 ° C; HPLC: 100%.

Example 7

3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-chlorobenzylamide

The product was obtained in a yield of 19% (0.040 g) according to the procedure of Example 1 but using 4-chlorobenzylamine and after crystallization from acetonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.45.

NMR: ^{DMSO; H} δ (ppm): 4.5 (d, 2H); 5.1 (s. 2H); 7.2-7.45 (m, 10H).

8.15 (d, 1H); 8.5 (s, 1H); 9.25 (t, 1H); 11.8 (bs, 1H).

IR 3365, 3200, 1726, 1638, 1551, 1512, 1444, 1305

1263, 1012, 844, 763 cm ^-1 ;

mp = 290.6 ° C; HPLC: 98.1%.

Example 8

3-Benzyl-2,4-diaxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methylbenzylamide

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The product is obtained in a yield of 19% (0.040 g) according to the procedure of Example 1 but using 4-methylbenzylamine and crystallization from acetonitrile.

TLC: CH ₂ C1 ₂ / MeOH 90: 5 Rf = 0.40.

NMR: DMSO ³ H δ (ppm) 2.3 (s, 3H); 4.4 (d, 2 H); 5.1 (s. 2H); 7.07.4 (m, 10H); 8.15 (d, 1H); 8.55 (s, 1H); 9.1 (t, 1H); 11.8 (bs, 1H).

IR: 3280, 1720, 1671, 1640, 1623, 1550, 1278, 848,

4,744 cm ^-1 ;

mp - 267.8 ° C; HPLC: 98.7%.

Example 9 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide

0.500 g (1.61 mmol) of the compound of Preparation C in 25 ml of anhydrous dimethylformamide was added to a 50 ml moisture-protected round-bottom flask with stirring. Then, 0.244 g (0.201 mL, 1.61 mmol) of piperonylamine and 0.531 g (1.61 mmol) of TOTU are added. The solution was cooled to 0 ° C in an ice bath and then 0.415 g (0.564 mL, 3.22 mmol) of N, N-diisopropylethylamine was added. The mixture was allowed to warm to room temperature and stirred overnight. After TLC analysis (90:10 CH ₂ Cl ₂ / MeOH), the dimethylformamide is removed in vacuo and the crystalline residue obtained is taken up in dichloromethane. The organic phase is washed successively with 1N HCl, water, saturated aqueous sodium hydrogen carbonate solution and finally with water again. The organic phase is dried over Na ₂ SO ₄ and the solvent is removed in vacuo. 0.540 g of product is obtained, which is recrystallized from acetonitrile to give 0.390 g of the title compound; yield = 54.6%.

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TLC: CH ₂ Cl ₂ / acetone 90/10 Rf = 0.40.

NMR: ^{DMSO; H} δ (ppm) 3.55 (s, 3H); 4.35 (d, 2 H); 5.15 (s. 2H); 6.0 (s. 2H); 6.75-6.95 (m, 3H); 7.2-7.4 (m, 5H); 7.55 (d, IH); 8.25 (d, 1H); 8.65 (s, 1H); 9.2 (t, 1H).

IR: 3303, 1703, 1656, 1637, 1498, 1444, 1322, 1254,

1040, 932, 845 cm ^-1 ;

mp = 215.1 ° C; HPLC: 99.5%.

Example 10

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide

The product is obtained with a yield of 56.8% (0,110 (g) the procedure of crystallization of Example 9 but in use from acetonitrile. benzylamine and AFTER TLC: CH ₂ Cl ₂ / acetone 90:10 R f = 0.55. NMR: CDCl ₃ δ (ppm) 3.65 (S, 3H); 4.65 (D, 2H) ; 5.3 (s. 2H); 6.55 (m, IH); 7.2-7.6 (m, 1H); 8.3 (d, 1H); 8 5 (s, 1H).

IR: 1708, 1655, 1641, 1616, 1507, 1478, 1326, 1246,

930,750 cm ^-1 ;

mp = 198.9 ° C; HPLC: 100%.

Example 11

Methyl 4 - ({[1- (3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl) methanoyl] amino} methyl) benzoate

The product was obtained in a yield of 61.5% (0.135 g) following the procedure of Example 9 but using methyl 4- (aminomethyl) -1-1 hydrochloride; 9-03-C benzoate and 3.5 equivalents of N, N-diisopropylethylamine. The crude product is purified by chromatography on silica gel using a 90: 5 CH ₂ Cl ₂ / MeOH gradient followed by crystallization in ether.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.36.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.85 (s, 3H); 4.55 (d, 2 H);

5.15 (s. 2H); 7.2-7.35 (m, 5H); 7.45 (d, 2 H); 7.6 (d, 1H); 7.95 (d, 2 H); 8.3 (d, IH); 8.65 (s, 1H); 9.35 (t, 1 H).

IR: 1123, 1706, 1657, 1642, 1617, 1506, 1477, 1284, 1109, 749 cm @ ^-1 ;

mp = 196 ° C; HPLC: 100%.

Example 12

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxy-3-methoxybenzylamide

The product was obtained in 42% yield (0.090 g) according to the procedure of Example 9 but using 4-hydroxy-3-methoxybenzylamine hydrochloride and 3.5 equivalents of N, N-diisopropylethylamine. The crude product is purified by chromatography on silica gel using a 90: 5 CH ₂ Cl ₂ / MeOH gradient followed by crystallization in ether.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.59.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.4 (d, 2 H);

5.15 (s. 2H); 6.75 (s. 2H); 6.95 (s, 1H); 7.2-7.40 (m, 6H); 7.55 (d, IH); 8.3 (d, IH); 8.65 (s, 1H); 8.8 (s, 1H); 9.15 (t, 1H).

IR: 1707, 1655, 1618, 1502, 1477, 1277, 704 cm ^-1 ;

mp = 183 ° C; HPLC: 87.1%.

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Example 13

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The product was obtained in a yield of 77.7% (0.320 g) according to the procedure of Example 9 but using 4-methoxybenzylamine. The crude product is purified by chromatography on silica gel using 97: 3 ΟΗ ₂ 01 ₂ / ΜθΟΗ. The desired fractions were combined and concentrated, the product crystallized from ether and then collected by filtration.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.8.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H);

5.2 (s. 2H); 6.9 (d. 2H); 7.2-7.4 (m. 7H); 7.6 (d, lH); 8.3 (d, lH);

8.65 (s, 1H); 9.25 (t, 1H).

IR: 1705, 1660, 1636, 1505, 1251, 750 cm ^{@ -1} ;

mp = 191 ° C; HPLC: 97.3%.

Example 14 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-pyridylmethyl) amide

The product was obtained in a yield of 67.7% (0.130 g) according to the procedure of Example 9 but using 4-picolylamine. The crude product is chromatographed on silica gel with an eluent 90: 5 CH ₂ Cl ₂ / MeOH. The desired fractions were combined and concentrated. The product precipitated in ether and then collected by filtration.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.18.

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NMR: DMSO ¹ H δ (ppm): 3.60 (s, 3H); 4.55 (d, 2 H); 5.15 (s. 2H);

7.2-7.4. (M, 7 H); 7.6 (d, 1H); 8.3 (d, 1H); 8.5 (d. 2H); 8.65 (s, 1H); 9.35 (t, 1 H).

IR: 1705, 1658, 1634, 1508, 1332, 831, 749, 705 cm @ ^-1 ;

mp 172 ° C; HPLC 98.8%.

Example 15 1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydroquinosoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

Step 1: Methyl 2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylate

0.750 g (3.6 mmol) of the compound of Preparation A and 7.5 ml of pyridine are introduced into a round-bottomed flask. Then 0.530 g (0.5 ml; 3.6 mmol) of phenethyl isocyanate is added. The mixture was left overnight at 100 ° C. Since the reaction is not complete, a second portion of phenethyl isocyanate is added, i.e. a 2. 2 equivalents. After precipitation with water, filtration and purification by suspending in hot ethanol, 0.640 g of product is obtained, yield = 54.9%.

NMR: DMSO ¹ H δ (ppm): 2.85-2.95 (m; 2H); 4.90 (s, 3H); 4.05-4.15 (m. 2H); 7.15-7.3 (m. 6H); 8.15 (d, IH); 8.45 (s, 1H); 11.8 (bs, 1H).

Step 2: 2,4-Dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

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The product from the previous step is hydryzed to the acid by the procedure of Step 2-4 of Preparation B to give 0.500 g of the desired compound (yield: 80%).

NMR: DMSO ² H δ (ppm) 2.85-2.95 (m, 2H); 4.05-4.15 (m. 2H); 7,157.3 (m, 6H); 8.15 (d, 1H); 8.45 (s, 1H); 11.75 (s, 1H); 13.05 (bs, 1H).

Step 3: 2,4-Dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide

The product was obtained in a yield of 57.8% (0.205 g) by the procedure of Example 1 using 250 mg (0.8 mmol) of the compound obtained in the previous step 2 and piperonylamine.

NMR: DMSO ² H δ (ppm): 2.9 (t, 2H); 4.1 (t. 2H); 4.4 (d, 2 H); 5.95 (s, 2 H); 6.75-6.95 (m, 3H); 7.15-7.35 (m, 6H); 8.1 (d, IH); 8.5 (s, 1H); 9.1 (t, 1H); 11.65 (bs, 1H).

IR: 3249, 1704, 1658, 1636, 1488, 1251, 810, 753 cm ^-1 ;

mp = 296 ° C; HPLC: 99.5%.

Step 4: 1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide

To a 25 ml round-bottomed flask was charged 0.190 g (0.46 mmol) of the product from previous step 3, 2 ml of dimethylformamide and

0.095 g (0.68 mmol) of K 2 CO 3. The mixture was stirred at room temperature for 15 min and then 0.325 g (0.15 mL, 2.29 mmol) of iodomethane was added. Stirring is continued for 30 to 45 minutes. The solvent was removed in vacuo, the residue was taken up in dichloromethane and washed with water. The organic phase was separated and dried over Na ₂ SO ₄ . After concentration in vacuo, the product is purified by chromatography on silica gel with 98: 2 CH 2 Cl ₂ / MeOH, and then

01-1699-03-Ce precipitated in ether to give 0.080 g of the desired compound (yield: 76%).

NMR: ^{DMSO; H} δ (ppm): 2.9 (t, 2H); 3.55 (s, 3H); 4.15 (t. 2H); 4.4 (d, 2 H); 5.95 (s, 2 H); 6.8-6.95 (m. 3H); 7.15-7.35 (m, 5H); 7.55 (d, IH); 8.25 (d, 1H); 8.6 (s, 1H); 9.15 (t, 1H).

IR: 3272, 1705, 1664, 1635, 1501, 1254, 1041, 751, 698 cm @ ^-1 ;

mp = 183 ° C; HPLC 99.7%.

Example 16 3- (4-Methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

Step 1: methyl 3- (4-methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The product was obtained in a yield of 61.3% (0.750 g) by the procedure of Step 1 of Example 15 but using 4-methoxybenzyl isocyanate.

NMR: ^{DMSO; H} δ (ppm): 3.7 (s, 3H); 3.8 (s, 3 H); 5.0 (s. 2H); 6.86.95 (m, 2 H); 7.2-7.3 (m. 3H); 8.1-8.2 (m, IH); 8.5 (s, 1H); 11.9 (bs, 1H).

Step 2: 3- (4-Methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product of the previous step 1 is hydrolyzed to the acid by the process of step 2-4 of preparation E to obtain 0.680 g of the desired compound (yield: 94.8%).

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NMR: ^{DMSO; H} δ (ppm): 3.7 (s, 3H); 5.0 (s. 2H); 6.8-7.9 (m. 2H);

7.2-7.3 (m. 3H); 8.1-8.2 (m, IH); 8.5 (s, 1H); 11.8 (s, 1H); 13.1 (bs, 1H).

Step 3: 3- (4-methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in a yield of 79.9% (0.220 g) according to the procedure of Example 9 using 200 mg (0.6 mmol) of the compound obtained in the previous step 2 and piperonylamine. The crude product is precipitated in dichloromethane.

NMR: ^{DMSO; H} δ (ppm): 3.7 (s, 3H); 4.35 (d, 2 H); 5.0 (s. 2H); 5.95 (s, 2 H); 6.75-6.9 (m, 5H); 7.2-7.3 (m. 3H); 8.1 (d, 1H); 8.5 (s, 1H); 9.1 (t, 1H); 11.75 (s, 1H).

IR: 1720, 1648, 1634, 1504, 1442, 1300, 1250, 1036,

66 cm ^-1 ;

mp = 252 ° C; HPLC: 96.2%.

Example 17 3- (4-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide

Alkylation of the product obtained in Example 16 with methyl iodide was carried out using the procedure of Example 15, step 4. The product was obtained after crystallization from ether: 0.080 g (yield: 70.4%).

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 4.4 (d, 2 H); 5.05 (s, 2 H); 5.95 (s, 2 H); 6.8-6.95 (m, 5H); 7.3 (d, 2 H); 7.55 (d, IH); 8.25 (d, 1H); 8.6 (s, 1 H); 9.2 (t, 1 H).

01-1699-03-Cic spectrum: 3265, 1704, 1662, 1634, 1504, 1443, 1320, 1248,

104 0.777 cm @ ^-1 ;

mp = 278 ° C; HPLC: 99.2%.

Example 18

3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Step 1: 3- (4-Methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-methoxybenzyl) amide

The product was obtained in a yield of 82% (0.270 g) by the procedure of Example 9 using 240 mg (0.74 mmol) of the compound obtained in Step 2 of Example 16 and 4-methoxybenzylamine.

NMR DMSO δ (ppm): 3.7 (2s, 6H); 4.4 (d, 2 H); 5.0 (s. 2H); 6.86.95 (m, 4H); 7.2-7.35 (m, 5H); 8.15 (d, 2 H); 8.5 (s, 1H); 9.15 (t, 1H); 11-75 (bs, 1H).

Step 2: 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The product was obtained in a yield of 94.4% (0.260 g) by the procedure of Example 15, Step 4, using the compound obtained in the previous Step 1.

NMR: DMSO δ (ppm): 3.6 (s, 3H); 3.7 (dd, 6H); 4.45 (d, 2 H); 5.1 (s. 2H); 6.8-6.95 (m, 4H); 7.25-7.40 (m, 4H); 7.55 (d, IH); 8.25 (d, 1H); 8.65 (s, 1H); 9.2 (t, 1H).

IR: 1705, 1655, 1641, 1614, 1510, 1247, 1175,

1033 cm ^-1 ;

mp = 195 ° C; HPLC: 99.5%.

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Example 19 3- (1-Naphth-1-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained according to the procedure of Example 16, steps 1 to 3, using 1- (1-naphthyl) ethyl isocyanate in step 1.

NMR: DMSO δ (ppm): 1.95 (d, 3H); 4.35 (d, 2 H); 6.0 (s. 2H);

6.7-6.8 (m. 2H); 6.8-6.9 (m. 2H); 7.2 (d, 1H); 7.4-7.5 (m, 2H);

7.6 (t, 1H); 7.85-8.0 (m, 5H); 8.10 (d, IH); 8.45 (s, 1H); 9.10 (t, 1 H); 11.6 (bs, 1H).

Example 20 2,4-Dioxo-3- (pyrid-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

Step 1: Dimethyl 4- (3-pyrid-4-ylmethylureido) isophthalate

The product is obtained in a yield of 94.2% according to the procedure of Step 1-5 of Preparation B using the compound obtained in Preparation A and

4-pyridine methylamine.

NMR: DMSO δ (ppm): 3.8 (s, 3H); 3.9 (s. 3H); 4.3 (d, 2 H); 7.307.35 (m, 2H); 8.0-8.1 (m, 1H); 8.4 (t, 1H); 8.5-8.6 (m, 4H); 10.3 (s, 1H).

Step 2: methyl 2,4-dioxo-3- (pyrid-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate

The product is obtained by the procedure of step 2-5 of Preparation B using the compound obtained in the previous step 1.

DMSO N δ (ppm): 3.85 (s, 3H); 5.1 (s. 2H); 7.20-7.30 (m, 3H); 8.2 (d, 1H); 8.4-8.5 (m. 3H); 11.95 (bs, 1H).

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100

Step 3: 2,4-dioxo-3- (pyrid-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product is obtained by the procedure of Step 2-4 of Preparation B using the compound obtained in the previous Step 2.

NMR: DMSO δ (ppm): 5.1 (s, 2H); 7.20-7.30 (m, 3H); 8.2 (d, 1H);

8.4-8.5 (m. 3H); 11.9 (s, 1H); 13.1 (bs, 1H).

Step 4: 2,4-dioxo-3- (pyrid-4-yimethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in 26.7% yield (0.850 g) by the procedure of Example 1 using the compound obtained in the previous step 3 and piperonylamine. After filtering off the insoluble material, the dimethylformamide is removed in vacuo. The residue is precipitated in dichloromethane.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.40.

NMR: DMSO δ (ppm): 4.40 (d, 2H); 5.0 (s. 2H); 5.95 (s, 2 H);

6.80-6.9 (m, 3H); 7.20-7.30 (m, 3H); 8.1-8.2 (m, 1H); 8.4-8.5 (m. 3H); 9.1 (t, 1H); 11.8 (s, 1H);

IR: 3267, 1713, 1645, 1626, 1444, 1313, 1040, 920,

69 cm ^-1 .

mp = 291.2 ° C; HPLC: 87.7%.

Example 21

2,4-Dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide

Step 1: Methyl N-benzyl-6- (3-thien-2-ylmethylureido) isophthalate

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101

The product was obtained following the procedure of Step 1-5 of Preparation B using the compound obtained in Preparation A and 2-thiophenomethylamine.

NMR: DMSO ^{Χ Η δ} (ppm): 3.8 (s, 3H); 3.9 (s. 3H); 4.5 (d, 2 H); 6.97.0 (m, 2 H); 7.4 (m. 1H); 8.0-8.05 (m, 1 H); 8.4 (t, 1H); 8.5 (s, 1H); 8.6-8.65 (m, IH); 10.15 (s, 1H).

Step 2: methyl 2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate

The product is obtained by the procedure of step 2-5 of Preparation B using the compound obtained in the previous step 1.

NMR DMSO ³ Η δ (ppm): 3.8 (s, 3H); 5.25 (s, 2 H); 6.9 (d, 1H); 7.1 (s, 1H); 7.25 (d, 1H); 7.4 (d, IH); 8.1-8.15 (m, 1H); 8.5 (s, 1H); 11.9 (bs, 1H).

Step 3: 2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The product is obtained by the procedure of Step 2-4 of Preparation B using the compound obtained in the previous Step 2.

NMR: DMSO ³ Η δ (ppm): 5.25 (s, 2H); 6.95 (d, IH); 7.15 (d, 1H); 7.2-7.3 (m. 1H); 7.4 (d, IH); 8.1-8.2 (m, IH); 8.5 (s, 1H); 11.9 (s, 1 H); 13.1 (bs, 1H).

Step 4: 2,4-Dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide

The product was obtained in 61.9% yield (0.160 g) by the procedure of Example 1 using the compound obtained in the previous step 3 and benzylamine. TLC: tBrCl / MeOH 90: 5 Rf = 0.8.

NMR: DMSO ¹ H δ (ppm): 4.50 (d, 2H); 5.2 (s. 2H); 6.90-7.4 (m, 9H); 8.15 (d, 1H); 8.6 (s, 1H); 9.2 (t, 1H); 11.8 (s, 1H);

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102

IR 3185, 1/30, 1646, 1633, 1512, 1446, 1292, 1260,

5,763 cm ^-1 ;

mp = 264.8 ° C; HPLC: 99.5%.

Example 22

1-Methyl-2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide

The product was obtained in 87% yield (0.090 g) by the procedure of Example 15 using the compound obtained in Example 21.

TLC: CH ₂ Cl ₂ / MeOH 90: 5, Rf = 0.8.

NMR: DMSO δ (ppm): 3.6 (s, 3H); 4.50 (d, 2 H); 5.3 (s. 2H);

6.90-7.0 (m, 1H); 7.2-7.5 (m. 7H); 7.55 (d, 1H); 8.3 (d, 1H); 8.7 (s, 1 H); 9.25 (t, 1 H).

IR: 3257, 1704, 1657, 1637, 1513, 1490, 1325, 1251, 829, 777 cm ^-1 ;

mp = 223.7 ° C; HPLC: 99.9%.

Example 23 2,4-Dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in a yield of 59% (0.170 g) by the procedure of Example 1 using the compound obtained in Step 3 of the example and piperonylamine. The crude product is precipitated in dichloromethane.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.4.

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103

NMR: DMSO ^{Χ Η δ} (ppm): 4.40 (d, 2H); 5.25 (s, 2 H); 6.0 (s. 2H);

6.75-7.0 (m, 4H); 7.1 (s, 1H); 7.25 (d, IH); 7.40 (d, IH); 8.2 (d, 1 H); 8.55 (s, 1H); 9.20 (t, 1H); 11.8 (s, 1H).

IR: 3185, 1727, 1632, 1502, 1445, 1300, 1259, 1040,

936, 846, 765 cm ^-1 ;

mp = 270.1 ° C; HPLC 95.2%.

Example 24 1-Methyl-2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in 79.7% yield (0.085 g) according to the procedure of Step 4 of Example 15 using the compound obtained in Example 23.

TLC: CH ₂ Cl ₂ / MeOH 90: 5, Rf = 0.8.

NMR: DMSO ^: δ (ppm): 3.6 (s, 3H); 4.40 (d, 2 H); 5.30 (s, 2 H); 6.0 (s. 2H); 6.8-7.0 (m, 4H); 7.2 (d, 1H); 7.40 (d, IH); 7.5-7.6 (m, 1H); 8.2-8.30 (m, 1H); 8.6 (s, 1H); 9.20 (t, IH).

IR: 3251, 1705, 1659, 1635, 1501, 1446, 1328, 1253,

1041, 926, 784 cm ^-1 ;

mp = 224.2 ° C; HPLC: 99.8%.

Example 25 3- (4-Chlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in a yield of 67.8% (0.170 g) following the procedure of Example 15, steps 1 to 3, when used in the first step of the compound.

01-1699-0

4 obtained in Preparation A and 4-chlorobenzyl isocyanate. The product is obtained after precipitation in dichloromethane.

NMR: DMSO δ (ppm): 4.35 (t, 2H); 5.1 (s. 2H); 5.95 (s, 2 H);

6.75-6.9 (m, 3H); 7.25 (d, 1H); 7.35 (s, 4H); 8.15 (d, IH); 8.5 (s, 1H); 9.15 (t, 1H); 11.8 (bs, 1H).

IR: 3265, 1734, 1653, 1633, 1504, 1440, 1254, 1041,

811, 761 cm ^-1 ;

mp = 290 ° C; HPLC: 99.2%.

Example 26 3- (4-Chloro-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide

The product was obtained in a yield of 88.9% (0.085 g) by the procedure of Example 15, Step 4, using the compound obtained in Example 25. The product was isolated by crystallization in ether.

NMR: DMSO δ δ (ppm): 3.55 (s, 3H); 4.40 (t, 2 H); 5.15 (s. 2H); 5.95 (s, 2K); 6.75-6.9 (m, 3H); 7.35 (s. 4H); 7.55 (d, IH); 8.25 (d, IH); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 3249, 1704, 1658, 1636, 1488, 1251, 810, 753 cm ^-1 ;

mp = 231 ° C; HPLC: 99.6%.

Example 27 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,31-dioxol-5-ylmethyl] -amide

The product was obtained (0.035 g) according to the procedure of Example 20, steps 1 to 4, using in the first step the compound obtained in Preparation A and monomethylamine and in step 4 the piperonylanine for amidation.

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105

TLC: CH ₂ Cl ₂ / MeOH 96/10 Rf = 0.50.

NMR DMSO 1 H δ (ppm): 3.35 (s, 3H); 3.55 (s, 3H); 4.40 (d, 2 H); 6.0 (s. 2H); 6.75-6.95 (m, 3H); 7.55 (d, IH); 8.25 (d, IH); 8.6 (s, 1 H); 9.25 (t, 1 H).

IR: 1703, 1649, 1501, 1486, 1256, 1037, 923 cm ^-1 ;

mp = 279 ° C; HPLC: 97.3%.

Example 28 Benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product was obtained in a yield of 36% (0.040 g) following the procedure of Example 20 of Steps 1 to 4 using in the first step the compound obtained in Preparation A and piperonylamine and in Step 4 piperonylamine for amidation.

Step 1: dimethyl-4- (3-benzo [1,3] dioxol-5-ylmethylureido) isophthalate

NMR CDC1 ₃ ^X H δ (ppm): 3.9 (s, 6H); 4.4 (s. 2H); 5.1 (t, 1 H);

6.70-6.85 (m, 3H); 6.95 (s, 2 H); 8.1-8.2 (m, 1H); 8.6-8.7 (s. 2H);

10.6 (bs, 1H).

Step 2: methyl 3- (benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

NMR: DMSO ^X H δ (ppm): 3.8 (s, 3H); 5.0 (s. 2H); 5.9 (s. 2H); 6.8 (s. 2H); 6.9 (s, 1H); 7.25 (d, IH); 8.15 (d, 1H); 8.5 (s, 1H); 11.8 (bs, 1H).

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Step 3: 3- (Benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

NMR: DMSO δ (ppm): 5.0 (s, 2H); 6.0 (s. 2H); 6.8 (s. 2H); 6.9 (s, 1H); 7.3 (d, IH); 8.2 (d, 1H); 8.5 (s, 1H); 11.85 (s, 1H);

13.05 (bs, 1H).

Step 4: 3- (Benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6 (benzo [1,3] dioxol-5-ylmethyl) amide -carboxylic acid

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: DMSO δ (ppm): 4.40 (s, 2H); 5.0 (s. 2H); 5.9 (s, 4H);

6.75-6.95 (m, 6H); 7.20-7.30 (m, 1H); 8.05-8.15 (m, 1H); 8.458.55 (m, IH); 9.1 (m, 1H); 10.3 (m, IH).

IR: 3271, 1739, 1649, 1630, 1503, 1440, 1250, 1041,

6,759 cm ^-1 ;

mp 245.2 ° C; HPLC: 81.5%.

Example 29 3- (Benzo [1,3] dioxol-5-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4- (benzo [1,3] dioxol-5-ylmethyl) amide tetrahydroquinazoline-6-carboxylic acid

The product was obtained in a yield of 40.5% (0.050 g) by the procedure of Example 15, Step 4, using the compound obtained in Example 28.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

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NMR: ^DMSO: Η δ (ppm): 3.55 (s, 3H); 4.35 (s, 2 H); 5.0 (s. 2H); 6.0 (s, 4 H); 6.80-7.0 (m, 6H); 7.5 (d, 1 H); 8.25 (d, IH); 8.6 (s, 1H);

9.15-9.2 (m, IH).

IR: 3302, 1703, 1663, 1630, 1490, 1247, 1041, 929,

807, 785 cm ^-1 ;

mp 197.5 ° C; HPLC: 100%.

Example 30 3-Benzyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

To a round-bottomed flask with moisture protection was added 0.150 g (0.35 mmol) of the compound of Example 2, followed by 3 ml of anhydrous dimethylformamide, with stirring. 0.075 g (0.525 mmol) of K 2 CO 3 is then added. The mixture was stirred for 15 min and then iodoethane (0.273 g, 0.14 mL, 1.75 mmol) was added. Stirring is continued for 1 h. The solvent was then removed in vacuo and the residue was dissolved in 50 mL of dichloromethane and washed with 2 x 50 mL of water, then dried over Na ₂ SO ₄ and concentrated in vacuo. The product is crystallized from 8 ml of acetonitrile to give 0.070 g of the title compound; yield = 43.7%. TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: ^{DMSO; H} δ (ppm): 1.25 (t, 3H); 4.2 (q, 2 H); 4.4 (d, 2 H); 5.15 (s. 2H); 5.95 (s, 2 H); 6.75-6.95 (m, 3H); 7.2-7.4 (m, 5H); 7.65 (d, 1H); 8.25 (d, IH); 8.65 (s, 1H); 9.15 (t, 1H).

IR: 1701, 1658, 1633, 1506, 1488, 1458, 1246, 1217,

1038, 926, 803 cm ^-1 ;

mp = 176.5 ° C; HPLC: 99%.

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Example 31 3-Benzyl-1-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzoyl, 3] dioxol-5-ylmethyl) amide

The product was obtained in a yield of 76.8% (0.130 g) following the procedure of Example 30 using cyclopropylmethyl bromide. The product is

obtained after precipitation in diisopropylether. TLC: CH ₂ Cl ₂ / MeOH 90: Δ Rf = 0.70. NMR: DMSO ³ Η δ (ppm) i: 0.4-0.55 (m, 4H); 1.25 (m, 1 H); 4.1 (d, 2 H); 4.35 (d, 2H); 5.15 (S, 2H); 5.95 (s (2H); 6.85 (m. 3H); 7.3 (M, 5H); 7.7 (d, 1 H); 8.25 (d, IH); 8.65 (S, 1H) ; 9.2 (t, 1 H). IR: 1703, 1656, 1641, 1505, 1467 1307, 1261, 1241 1043, 936, 845, 748 cm ^-1 ;

mp = 184.4 ° C; HPLC: 97.2%.

Example 32 3-Benzyl-1-isobutyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

The product is with a yield of 35.3% (0.060 g) procedure from Example 30 at use of isobutyl bromide. TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf 0.65. NMR: CDCl ₃ ^Χ Η δ (ppm) 1.0 (d, 6 H); 2.15 (m, 1H); 4.0 (D 2 H); 4.5 (d, 2H); 4.25 (; s, 2H); 5.95 (s, 2H); 6.55 (M, 1H); 6.8 (m, 3 H);

7.25 (m, 4H); 7.45 (d, 2 H); 9.25 (t, 1H); 8.45 (s, 1H).

IR: 1705, 1660, 1643, 1548, 1502, 1456, 1303, 1260, 1245, 1043, 92 3 cm ^-1 ;

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109 mp = 146.0 ° C; HPLC: 96.8%.

Example 33 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide

Step 1: methyl 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

A mixture of 0.870 g (1.7 mmol) of the compound obtained in Step 1 of Preparation C, 20 ml of benzene and 2.1 g (16.1 mmol) of AlCl 3 was left at 50 ° C for 7 h. After cooling, the mixture was precipitated with a mixture of water and ice. The insoluble material was dissolved in dichloromethane and purified on silica gel using a gradient of CH ₂ Cl ₂ / acetone. 0.510 g of the desired compound is obtained.

Step 2: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide

Hydrolysis of the compound obtained in the previous step 1 is carried out with LiOH in dioxane / water as in the previous example. Amidation with piperonylamine gives 0.160 g of the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.45.

NMR: ^{DMSO; H} δ (ppm) 3.45 (s, 3H); 4.4 (d, 2 H); 6.0 (s. 2H);

6.75, -6.95 (m, 3H); 7.5 (d, 1 H); 8.25 (d, IH); 8.55 (s, 1H); 9.2 (t, 1 H); 11.7 (s, 1 H).

IR: 3290, 1697, 1635, 1503, 1484, 1324, 1258, 1040, 844 cm ^-1 ;

mp = 279 ° C; HPLC: 98.7%.

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Example 34

Methyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethylbenzoate

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Preparation was the same as in Example 33 using 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (NMR: DMSO- d 6 ppm) 3.50 (s, 3H) 7.5 (d, 1H); 8.20 (d, 1H); 8.50 (s, 1H); 11.75 (bs, 1H); 13.1 (bs, 1H)) and 4- methoxybenzylamine in dimethylformamide with TOTU and DIPEA.

NMR: DMSO δ (ppm) 3.50 (s, 1H); 3.70 (s, 3H); 4.40 (d, 2 H);

6.90 (d, 2 H); 7.25 (d, 2 H); 7.50 (d, IH); 8.20 (d, IH); 8.55 (s, 1H); 9.20 (t, 1H); 11.65 (bs, 1H).

Step 2: methyl 4- (6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl) benzoate

A mixture of 0.8 g (2.36 mmol) of the product obtained in the previous step 1 and 8 ml of anhydrous dimethylformamide was stirred with 1.15 g (3.54 mmol) of cesium carbonate. Stirring is continued for 15 minutes and then 0.81 g (3.54 mmol) of methyl 4- (bromomethyl) beczoate is added and the mixture is left at 90 ° C for 1.25 hours and then stirred overnight. 15 ml of water are then added and the mixture is extracted with dichloromethane. The organic phase is washed with water and concentrated to dryness. The product is purified by chromatography on silica gel

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111 eluting with a gradient of CH ₂ Cl ₂ / MeOH to give 0.220 g of the title compound.

TLC: CH ₂ C1 ₂ / MeOH 90:10, Rf = 0.85.

NMR: DMSO ² Η δ (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 3.85 (s, 3H);

4.4 (d, 2 H); 5.25 (s, 2 H); 6.9 (d. 2H); 7.25 (d, 2 H); 7.45 (d, 2 H); 7.55 (d, 1H); 7.9 (d. 2H); 8.25 (dd, IH); 8.6 (s, 1H); 9.2 (t, 1H).

IR: 3387, 1709, 1658, 1642, 1508, 1286, 1248, 1110,

32, 835, 750 cm ^-1 ;

mp = 189.2 ° C; HPLC: 96.5%.

Example 35

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

A mixture of 0.16 g (3.3 mmol) of the product obtained in Example 34 is hydrolyzed with a mixture of 1.2 ml dioxane and 4.2 ml water with 28 mg of LiOH monohydrate. Heat the mixture to boiling for 10 min. After acidification to pH 1 with concentrated HCl, the precipitate was collected by filtration to give 0.120 g of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO 1 H δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.4 (d, 2 H);

5.20 (s, 2H); 6.9 (d. 2H); 7.25 (d, 2 H); 7.40 (d, 2 H); 7.60 (d, 1H); 7.85 (d, 2 H); 8.25 (dd, IH); 8.65 (s, 1H); 9.2 (t, 1H) 12.9 (bs, 1H).

IR 3378, 1702, 1658, 1645, 1616, 1506, 1297, 1248,

1125, 839, 788, 751 cm ^{@ -1} ;

mp = 262.5 ° C; HPLC 100%.

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Example 36 1-Methyl-2,4-dioxo-3 - ((E) -3-phenylalyl) -1,2,3,4-tetrahydroquinazoline-6- (benzo [1,3] dioxol-5-ylmethyl) amide carboxylic acid

A mixture of 0.100 g (0.28 mmol) of the compound of Example 33 and anhydrous dimethylformamide was stirred with 0.060 g (0.42 mmol) of K ₂ CO ₃ . The mixture was stirred for 15 min and then cinnamyl bromide (0.085 g, 0.42 mmol) was added. The mixture was left at 70 ° C for 2 h. After concentration in vacuo, the residue is taken up in dichloromethane, washed with water and then dried over Na ₂ SO ₄ . The solvent was removed and the product was purified by chromatography on silica gel eluting with a 90: 5 CH ₂ Cl ₂ / MeOH gradient. Precipitation in ether yields 0.070 g (yield = 51%) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.46.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 4.4 (d, 2 H); 4.75 (d, 2 H); 6.0 (s, 2n); 6.3-6.4 (m, IH); 6.6 (d, 1H); 6.80-6.95 (m, 3H); 7.2-7.35 (m, 3H); 7.4 (d, 2 H); 7.55 (d, IH); 8.25 (d, IH); 8.65 (s, 1H);

9.25 (t, 1 H).

IR spectrum 1659, 1643, 1503, 1477, 1246, 754 cm ^-1 ;

mp = 174 ° C; HPLC: 98.4%.

Example 37

Benzyl 3-benzyl-2,4-dioxo-2,3,4-tetrahydroquinazoline-6-carboxylate

A mixture of 0.5 g (1.7 mmol) of the compound of Preparation B, 0.44 g (1.7 mmol) of triphenylphosphine and 0.44 ml (4.3 mmol) of benzyl alcohol is stirred in 20 ml of THF. A solution of 0.27 ml (1.1 mmol) of DEAD in 10 ml of tetrahydrofuran is then added dropwise with stirring.

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Stirring is continued overnight at room temperature. The precipitate was collected by filtration through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate and washed successively with water and then with a saturated aqueous sodium chloride solution. After drying over MgSO ₄ and concentration in vacuo, the crude product is purified by chromatography on silica gel, eluting with 50:50 hexane / EtOAc. The desired fractions were combined and the solvent removed in vacuo to give 0.190 g (yield = 29%) of the desired crystalline compound.

mass spectrum: m / z 387.2 (M + H) &lt; + &gt;.

NMR: DMSO δ (ppm): 5.06 (s, 2H); 5.34 (s, 2 H); 7.22-7.46 (m, 10H); 8.20 (d, IH); 8.48 (s, 1H); 11.89 (s, 1H).

CHN analysis (C ₂₃ H ₈ N ₂ O ₄ ) calculated (%): 0 = 71.49, H = 4.70, N = 7.25;

found (%): 0 = 71.28, H = 4.94, N = 7.1.

Example 38

Benzyl-3-methyl-benzy1-1-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-carboxylate

A mixture of 0.084 g (0.217 mmol) of the product of Example 37 and anhydrous tetrahydrofuran was stirred in a moisture protected apparatus and an inert atmosphere. 0.14 ml of a 1.6 M solution of BuLi in hexane (0.224 mmol) is then added. The mixture was stirred for 10 minutes and then methyl iodide (0.04 mL, 0.642 mmol) was added. TF was removed in vacuo and the residue was dissolved in EtOAc and washed sequentially with water followed by saturated aqueous chloride solution.

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114 sodium. After drying over _MgSO4 and concentration in vacuo, the crude product is purified by chromatography on silica gel with 50:50 hexane / EtOAc. The desired fractions were combined and the solvent removed in vacuo. The pale yellow product is precipitated in ether to give 0.049 g of the desired compound, yield = 56%.

Mass spectrum: m / z 401.2 (M + H) +.

^X H NMR DMSO δ (ppm): 3.31 (s, 3H); 5.12 (s. 2H); 5.37 (s, 2 H);

7.21-7.60 (m, 11H); 8.28 (d, IH); 8.58 (s, 1H).

CHN analysis (C 24 H 20 N 2 O 4) calculated (%): C = 71.99, H = 5.03,

N = 7.00; Found (%): C = 71.71, H = 5.25, N = 6.87.

Example 39

4-Pyridylmethyl 3-benzyl-2,4-dioxo-2,3,4-tetrahydroquinazoline-6-carboxylate

The compound was obtained according to the procedure of Example 37 but using dichloromethane as solvent, mass spectrum of product: m / z 388.2 (M + H) +.

DMSO ^X H δ (ppm): 5.07 (s, 2H); 5.41 (s. 2H); 7.20-7.32 (m, 6H);

7.43 (d, 2 H); 8.26 (d, IH); 8.53-8.58 (m, 3H); 11.93 (s, 1K).

CHN Analysis (C22H17N3O4.0, 3H ₂ O) Calcd (%): C, 67.27; H, 4.52;

N = 10.70; Found (%): C = 67.32, H = 4.40, N = 10.47.

Example 40

4-Pyridylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbuylate

The compound was obtained by the procedure of Example 37 but using the compound of Preparation C and 4-pyridylcarbinol.

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Mass spectrum: m / z 402.3 (M + H) +.

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 5.14 (s, 2 H); 5.42 (s, 2 H);

7.23-7.33 (m, 5H); 7.43-7.45 (m, 2 H); 7.60 (d, 1H); 8.32-8.36 (m, IH); 8.57-8.64 (m, 3H).

CHN analysis (C 23 H ₁₉ N ₃ O ₄ .0.14 H ₂ O): calculated (%): C 68, 39, H 4.81, N 10.40; Found (%): C 68.40, H 4.71, N 10.38.

Example 41

Benzo [1,3] dioxol-5-ylmethyl-3-benzyl-2,4-dioxo-2,3,4-tetrahydroquinazoline-6-carboxylate

To a round-bottomed flask protected from moisture was charged 0.100 g (0.337 mmol) of the compound of Preparation B and 1 ml of anhydrous THF. The suspension was stirred and 0.24 g (0.150 mL, 2.025 mmol) of t-ionyl chloride was added. The mixture was then heated to boiling for 1.5 h. After cooling, the solution was concentrated to dryness and the resulting 0.110 g of the acid chloride was used in the next step without further purification.

To a round-bottomed flask protected from moisture was added 0.080 g (0.51 mmol) of piperonyl alcohol and 1 mL of dichloromethane and 0.051 g (0.070 mL, 0.51 mmol) of triethylamine. The solution is cooled to 0 ° C and a mixture of the above acid chloride in 2.5 mL of dichloromethane is added. The mixture was then stirred at room temperature for 48 h. The resulting precipitate was collected by filtration and 0.050 g of crude product was purified by recrystallization from acetonitrile. Yield 0.025 g; 17%; TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.85.

NMR DMSO ^{Χ Η δ} (ppm): 5.1 (s, 2H); 5.25 (s, 2H); 6.05 (s, 2 H); 6.97.4 (m, 9H); 8.2 (d, 1 H); 8-5 (s, 1H); 11.9 (bs, 1H).

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IR: 1715, 1656, 1624, 1446, 1285, 1262, 1080, 928,

65, 7 64 cm ^-1 ;

mp = 238.5 ° C; HPLC: 99.7%.

Example 42

Benzo [1,3] dioxol-5-ylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound was obtained (0.140 g) according to the procedure of Example 41 but using the compound of Preparation C and piperonyl alcohol.

TLC CH ₂ Cl ₂ / MeOH 90: 5 R f = 0.85.

NMR: ^{DMSO; H} δ (ppm) 3.55 (s, 3H); 5.15 (s. 2H); 5.30 (s, 2 H); 6.05 (s, 2 H); 6.9-7.4 (m. 8H); 7.6 (d, IH); 8.25 (d, 1H); 8.6 (s, 1 H).

IR: 1716, 1703, 1659, 1618, 1447, 1294, 1227, 1103,

935, 813, 763 cm ^-1 ;

mp = 199.5 ° C; HPLC: 98.8%.

Example 43

Benzyl-1-benzyl-2,4-dioxo-3-pyrid-4-ylmethyl-1,2,3,4-tetrahydroquinazoline-6-carboxylate

A mixture of 0.5 g (1.7 mmol) of the compound obtained in Step 3 of Example 20 and 15 ml of anhydrous THF was added with stirring to 0.2 ml (1.7 mmol) of benzyl chloride and 1.2 g (8.7 mmol) of K. ₂ CO ₃ . The mixture was stirred at room temperature overnight. Conventional work-up yields the title compound.

Mass Spectrum: m / z 478.2 (M + H) +.

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NMR: DMSO δ (ppm): 5.19 (s, 2H); 5.35 (s, 2H); 5.39 (s. 2H);

7.25-7.45 (m, 13H); 8.19 (d, 1H); 8.47-8.49 (m, 2 H); 8.62 (s, 1H).

CHN analysis (C 29 H 23 N 3 O 4) calculated (%): 0 = 72.94, H = 4.85, N = 8.80;

found (%) 0 = 72.58, H = 4.79, N = 8.57.

Example 44

4-pyridylmethyl-2,4-dioxo-3- (2-thienyl ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate

The compound obtained in Step 3 of Example 21 (0.69 g; 2.3 mmol) was reacted as in Example 37 using 4-pyridylcarbinol.

Mass Spectrum: m / z 394.2 (M + H) +.

NMR: ^{DMSO; H} δ (ppm): 5.21 (s, 2H); 5.40 (s, 2 H); 6.93 (d, H); 7.11 (m, 1H); 7.28 (d, 1H); 7.40 (d, 1H); 7.40 (t, 2 H); 8.24 (d, IH); 8.49-8.59 (m, 3H).

CHN analysis for C 20 H 15 N 3 O 4 S. 0,13CH ₂ C1 ₂ .0,03éter O: C = 59.81; H, 3.86; N = 10.33; Found (%): C 59.79, H 3.82, N 10.32.

Example 45

4-pyridylmethyl-3- (benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-carboxylate

The title compound (0.040 g) was obtained according to the procedure of Example 37 but using the compound obtained in Step 28 of Example 28 and 4-pyridylcarbinol. The product is crystallized from methanol.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR DMSO ¹ H δ (ppm): 5.0 (s, 2H); 5.70 (s, 2 H); 6.0 (s. 2H); 6.85 (s, 2 H); 7.0 (s, 1H); 7.4 (d, 1H); 7.95-8.05 (m, 2H); 8.3-8.35 (m, 1H); 8.60 (s, 1H); 8.8-8.95 (m, 2 H); 12.0 (m, IH).

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IR: 1710, 1670, 1622, 1501, 1440, 1279, 1236, 1041,

3,77 64 cm ^-1 ;

mp = 204.4 ° C; HPLC: 92.4%.

Example 46

Benzyl 3-benzyl-2,4-dioxo-l, 2,3,4-tetrahydro-pyrido [2,3-d] pyrimidine-6-carboxylate

Step 1: 3-Benzyl-6-methyl-1H-pyrido [2,3-d] pyrimidine-2,4-dione

A mixture of 20 g (111 mmol) of ethyl 2-amino-5-methylnicotinate and 200 ml of pyridine is heated to boiling and then 13.7 ml (111 mmol) of benzyl isocyanate are added. Heating to boiling is continued overnight. After cooling, the precipitate was collected by filtration and washed with 2 x 100 ml ethanol and 2 x 100 ml ether. 10 g of product are obtained in two portions; yield 34%.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.5.

NMR: DMSO ¹ H δ (ppm): 2.2 (s, 3H); 5.0 (s. 2H); 7.15-7.35 (m, 5H); 8.1 (s. 1H); 9.5 (s, 1 H).

mp = 279 ° C; HPLC: 91%.

Step 2: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid

A round flask was charged with 3.0 g (11.2 mmol) of the product from previous step 1, 100 mL H ₂ O, 7.1 g (44.9 mmol) KMnO ₄ and mL NMP. The reaction mixture is heated at reflux overnight

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119 hot filters. The filtrate crystallizes upon cooling. The precipitate was collected by filtration and 40 ml of Amberlite IR 120 (+) resin was added to the filtrate. The resin was filtered and the acid and the acid is extracted by washing with 70:30 CH 2 Cl ₂ / MeOH. The solvent was removed in vacuo to give 0.32 g of a white solid (yield = 10%).

NMR: ^{DMSO; H} δ (ppm): 5.0 (s 2H); 7.15-7.25 (m, 5H); 8.65 (s, 1H); 9.1 (s, 1H); 12.4 (s, 1H).

Step 3: benzyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylate

ESterification of compound z is carried out as described in benzyl alcohol. After precipitation in the desired product (yield of previous step 2, Example 37 using methanol gave 0.040 g = 31%): TLC: CH ₂ Cl ₂ / MeOH 90: 5

Rt = 0.8.

NMR CDC1 ₃ ^LH δ (ppm): 5.2 (s, 2H); 5.4 (s. 2H); 7.2-7.6 (m, IH);

9.05 (s, 1H); 9.3 (s, 1H); 10.9 (s, 1H).

mp = 223 ° C; HPLC: 93.1%.

Example 47

4-Pyridylmethyl-3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylate

ABOUT

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120

The title compound is obtained in a yield of 20% (0.050 g) according to the procedure described in Example 37 but using the compound obtained in Step 2 of Example 46 and 4-pyridylcarbinol.

TLC: EtOAc / MeOH 99: 1 Rf = 0.6.

NMR DMSO δ (ppm): 5.05 (s, 2H); 5.4 (s. 2H); 7.15-7.41 (m, 5H); 7.45 (d, 2 H); 8.55 (d, 2 H); 8.7 (s, 1H); 9.15 (s, 1H); 12.55 (s, 1 H);

mp 280 ° C; HPLC: 97%.

Example 48 3-Benzyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide

H θ A H U Tf i \ n UL about ·' 0 The synthesis is carried out by of synthetic scheme 1, during

cyclization to 4-oxo-2-thioxoquinazoline, benzylisothiocyanate was used. After hydrolysis and amidation with piperonylamine it is obtained

0.100 g of the desired compound. TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.64. NMR: DMSO δ (ppm): 4.4 (d, 2H); 5.65 (s, 2 H); 5.95 (S, 2H); 6.75-6.95 (m, 3H); 7.2-7.4 (m, 5H); 7.45 (d, IH); 8.2 (D, 1H);

8.55 (s, 1H); 9.2 (t, 1H); 13.2 (bs, 1H).

IR: 1698, 1636, 1619, 1528, 1446, 1194, 1037, 768 cm @ ^-1 ;

mp 249 ° C; HPLC: 97.2%.

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Example 49

4- [6- (4-Hydroxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

0.7 g (1.44 mmol) of the compound of Example 34 and 70 ml of anhydrous dichloromethane are introduced into a moisture-protected round-bottomed flask with stirring. While stirring, 1.4 ml (14.4 mmol) of BBr ₃ in 7 ml of dichloromethane are added dropwise. After 2 h at room temperature, the reaction is complete. After usual work-up, 0.280 g of the desired compound is obtained, yield = 42%.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.15.

NMR: DMSO ² H δ (ppm): 3.55 (s, 3H); 4.35 (d, 2 H); 5.2 (s. 2H);

6.65 (d, 2 H); 7.10 (d, 2 H); 7.40 (d, 2 H); 7.55 (d, IH); 7.85 (d, 2 H); 8.25 (d, 1H); 8.60 (s, 1H); 9.15 (t, 1H); 9.2 (s, 1H); 12.8 (bs, 1H).

IR: 3403, 2553, 1697, 1658, 1615, 1507, 1482, 1423,

1247, 1109, 829, 752 cm ^-1 ;

mp = 174.0 ° C; TLC 97.06%.

Example 50

3- (4-Dimethylcarbamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Following the procedure described in Example 1, 0.3 g (0.64 mmol) of the compound of Example 35 and a 2M solution of dimethylamine in THF were reacted. The crude product is chromatographed on silica gel and precipitated in ether to give 0.160 of the desired compound (yield: 49.9%).

TLC: CH ₂ Cl ₂ / MeOH

90:10 R f = 0.70.

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NMR: CDCl _{3 3} H δ (ppm): 2.0 (s, 3H); 3.05 (s. 3H); 3.60 (s, 3H);

3.80 (s, 3K); 4.60 (d, 2 H); 5.25 (s, 2 H); 6.60 (t, 1H); 6.85 (a, 2 H); 7.3 (m, 5 H); 7.45 (d, 2 H); 8.25 (d, IH); 8.50 (s, 1H).

IR: 3378, 1710, 1654, 1641, 1618, 1508, 1476, 1246, 522 cm ^-1 ;

mp = 189 ° C; HPLC: 97%.

Example 51

1-Methyl-3- (4-methylcarbamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Example 50 but using methylamine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.55.

NMR: DMSO δ (ppm) : 2,75 (d, 3H); 3.55 (S, 3H); 3.70 (s, 3H); 4.40 (d, 2 H); 5,20 1 (s, 2H); 6, 85 (D, 2H) ; 7.25 (D, 2H) ; 7.35 (d, 2H); 7.55 (d, 1 H); 7.75 (D 2 H); 8.25 (q, 1 H); 8.35 (d, 1H);

8.60 (s, 1 H); 9.2 (t, 1 H).

IR: 3338, 1708, 1654, 1616, 1548, 1507, 1329, 1245,

1036, 825, 751 cm ^-1 ;

mp = 255.1 ° C; HPLC: 97.0%.

Example 52

3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and 3-allyl bromide.

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NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.8 (s, 3 H); 4.4 (d, 2 H); 4.55 (d, 2 H); 5.10-5.20 (m, 2 H); 5.80-5.95 (m, IH); 6.9 (d. 2H); 7.25 (d, 2 H); 7.55 (d, IH); 8.25 (d, IH); 8.6 (s, 1H); 9.25 (t, 1H).

IR: 1703, 1642, 1615, 1508, 1477, 1246, 765 cm @ ^-1 ;

mp 207 ° C; HPLC 98.9%.

Example 53

1-Methyl-2,4-dioxo-3- (2-pyrrol-1-ylethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 a

1- (2-bromoethyl) pyrrole.

NMR DMSO ^{Χ Η δ} (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 4.15 (m. 2H); 4.25 (m, 2 H); 4.40 (d, 2 H); 5.90 (s, 2H)); 6.7 (s. 2H); 6.90 (d, 2H); 7.25 (d, 2H); 7.55 (d, IH); 8.25 (d, IH); 8.55 (s, IH); 9.2 (t, 1H).

IR: 3338, 1708, 1655, 1640, 1508, 1478, 1251, 1117,

1032, 835, 734 cm ^-1 ;

mp = 147 ° C; HPLC 96.6%.

Example 54

1-Methyl-2,4-dioxo-3- (2-prop-2-ynyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and prop-2-ynyl bromide.

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NMR DMSO δ (ppm): 3.15 (s, 1H); 3.55 (s, 3H); 3.7 (s. 3H); 4.40 (d, 2 H); 4.70 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, IH);

8.25 (d, 1H); 8.60 (s, 1H); 9.25 (t, 1H).

IR: 3265, 1710, 1667, 1635, 1501, 1326, 1249, 1036,

5,783,725 cm ^-1 ;

mp = 206 ° C; HPLC: 97.7%.

Example 55

1-Methyl-3- (3-methylbut-2-enyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and 1-bromo-3-methylbut-2-ene.

NMR: ^{DMSO; H} δ (ppm): 1.65 (s, 3H); 1.75

3.7 (s. 3H); 4.40 (d, 2 H); 4.55 (d, 2 H) (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 1H); 8.25

9.25 (t, 1 H).

IR 3282, 1705, 1659, 1634, 1500, (s, 3K); 3.50 (s, 3H);

5.20 (t, 1H); 6.90 (d, IH); 8.60 (s, 1 H);

1314, 1246, 826 cm ^-1 ;

mp = 187 ° C; HPLC: 96.9%.

Example 56

1-Methyl-2,4-dioxo-3- (pyridin-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

2- (bromoethyl) pyridine.

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NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.7 (s, 3H);

5.25 (s, 2 H); 6.90 (d, 2 H); 7.25 (m, 3H); 7.35 (4.1H); 7.70 (m, IH); 8.25 (d, IH); 8.40 (d, 1H);

4.40 (d, IH);

(D, lH); 7.60

8.60 (s, 1H);

9.2 (t, 1H).

IR: 1702, 1658, 1643, 1618, 1508, 1476, 1331, 1248,

51 cm ^-1 ;

mp - 156 ° C; HPLC 99.5%.

Example 57

3-Carbamoylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

Of 2-chloroacetamide.

NMR DMSO ^{Χ Η δ} (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 4.40 (d, 2 H); 4.5 (s. 2H); 6.90 (d, 2 H); 7.20 (s, 1H); 7.25 (d, 2 H); 7.55 (d, 1H);

7.65 (s, 1H); 8.25 (d, IH); 8.60 (s, 1H); 9.25 (t, 1H).

IR: 1655, 1531, 1509, 1477, 1303, 1249, 752 cm @ ^-1 ;

mp = 269 ° C; HPLC: 99.2%.

Example 58

1-Methyl-2,4-dioxo-3- (pyridin-3-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

3- (bromomethyl) pyridine.

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DMSO δ (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 4.40 (d, 2 H); 5.20 (s, 2H); 6.85 (d, 2 H); 7.20-7.40 (m, 3H); 7.55 (d, 1H); 7.75 (d, 1H); 8.25 (m, 1H); 8.45 (d, 1H) 8.60 (m, 2H); 9.20 (t, 1H).

IR: 1699, 1660, 1615, 1500, 1479, 1249, 1032, 752,

712 cm ¹ ;

mp = 140 ° C; HPLC: 89.6%.

Example 59

1,1-Methyl-3- (1-methylpiperidin-3-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

3-bromomethyl-l-methylpiperidine.

NMR: ^{DMSO; H} δ (ppm): 0.85-1.00 (m, 1H); 1.30-1.45 2.05 (m, 5H); 2.10 (s. 3H); 2.60 (m, 2 H); 3.55 (s, 3H); 3.85 (d, 2 H); 4.40 (d, 2 H); 6.90 (d, 2 H);

7.50 (d, IH); 8.25 (d, IH); 8.60 (s, 1H); 9.25 (t, 1H) (m, 1H); 1.55 (s, 3H); 3.75

7.25 (d, 2H);

IR: 2926, 1655, 1641,

1508, 1247, 788 cm ^-1 ;

mp = 174 ° C; HPLC: 99.3%.

Example 60

3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and 4- (bromomethyl) benzonirrile.

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NMR: DMSO ³ H δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.40 (d, 2 H);

5.20 (s, 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.45-7.60 (m, 3H); 7.75 (d, 2 H); 8.25 (d, IH); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3411, 2216, 1708, 1649, 1616, 1251, 839, 765 cm ^{@ -1} ;

mp - 222 ° C; HPLC: 97.2%.

Example 61

3- (3-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

3- (bromomethyl) benzonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: ^{DMSO; H} δ (ppm): 3.45 (s, 3H); 3.70 (s, 3H); 4.45 (d, 2 H);

5.15 (s. 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (m. 2H); 7.70 (m, 2 H); 7.80 (s, 1H); 8.25 (d, 1H); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 1708, 1660, 1619, 1503, 1477, 1335, 1247, 1160,

952, 760, 718 cm ^-1 ;

mp 201 ° C; HPLC: 97.1%.

Example 62

3- (2-Methoxyethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and 1-bromo-2-methoxyethane.

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NMR: DMSO ¹ H δ (ppm): 3.25 (s, 3H); 3.55 (m, 5H); 3.70 (s, 3H);

4.15 (t. 2H); 4.40 (d, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 1H); 8.25 (d, 1H); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3274, 1709, 1660, 1633, 1514, 1249, 1030, 823 cm &^lt; -1 &gt;;

mp 200 ° C; HPLC: 99.2%.

Example 63

3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

3- (bromomethyl) -1-methoxybenzene.

NMR DMSO δ (ppm): 3.55 (s, 3H); 3.10 (s. 6H); 4.40 (d, 2 H);

5.10 (s. 2H); 6.75-6.90 (m, 5H); 7.15-7.30 (m, 3H); 7.55 (d, IH);

8.25 (d, IH); 8.60 (s, 1H); 9.20 (t, 1H).

IR 3387, 1704, 1657, 1640, 1616, 1509, 1250, 766 cm &^lt; -1 &gt;;

mp = 154 ° C; HPLC 99.4%.

Example 64

3-Cyclopropylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and bromomethylcyclopropane.

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NMR: ^{DMSO; H} δ (ppm): 0.40 (m, 4H); 1.2 (m, 1H); 3.55 (s, 3H);

3.70 (s, 3H); 3.85 (d, 2 H); 4.40 (d, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 1H); 8.25 (m, IH); 8.60 (d, 1H); 9.20 (t, 1H).

IR: 3282, 1703, 1657, 1634, 1502, 1258, 1028, 829,

752 cm ^-1 ;

mp = 209 ° C; HPLC: 98.2%.

Example 65

1-Methyl-3- (2-morpholin-4-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and 4- (2-bromomethyl) morpholine.

NMR: ^{DMSO; H} δ (ppm): 2.40 (m, 4H); 2.55 (m, 2 H); 3.50 (m, 7H); 3.75 (s, 3H); 4.10 (t. 2H); 4.40 (d, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 1H); 8.25 (d, 1H); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3419, 1707, 1656, 1612, 1506, 1475, 1246, 1111, 752 cm @ ^-1 ;

mp = 135 ° C; HPLC: 98.5%.

Example 66

3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and (bromomethyl) cyclohexane.

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NMR: DMSO ^: δ (ppm): 0.9-1.20 (m, 5H); 1.5-1.85 (m, 6H); 3.55 (s, 3H); 3.70 (s, 3H); 3.80 (d, 2 H); 4.40 (d, 2H); 6.90 (d, 2 H);

7.25 (d, 2 H); 7.50 (d, 1H); 8.25 (m, IH); 8.60 (s, 1H); 9.20 (t, IH).

IR: 3378, 2918, 1703, 1654, 1640, 1508, 1478, 1329,

1244, 789, 767 cm ^-1 ;

mp = 183 ° C; HPLC: 99.0%.

Example 67

1-Methyl-2,4, dioxo-3- (3-phenylpropyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound of Example 34, Step 1, a

3-phenylpropyl bromide.

NMR: DMSO ^{λ Η δ} (ppm): 1.90 (m, 2H); 2.65 (t, 2 H); 3.50 (s, 3H);

3.70 (s, 3H); 4.0 (t, 2 H); 4.40 (d, 2H); 6.85 (d, 2H); 7.10-7.30 (m, 7H); 7.50 (d, 1H); 8.20 (m, IH); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3395, 1704, 1641, 1615, 1509, 1477, 1327, 1245, 1032, 749 cm @ ^-1 ;

mp - 167 ° C HPLC: 98.8%.

Example 68

3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid methoxybenzylamide

The title compound is obtained according to the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and 4- (bromomethyl) fluorobenzene.

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NMR DMSO ^{Χ Η δ} (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H); 5.1 (s. 2H); 6.90 (d, 2 H); 7.10 (t, 2 H); 7.25 (d, 2 H); 7.40 (m, 2 H);

7.50 (d, IH); 8.25 (m, IH); 8.60 (s, 1H); 9.20 (t, IH).

IR: 3395, 1704, 1641, 1615, 1509, 1477, 1327, 1245,

1032, 74 9 cm ^-1 ;

mp = 180 ° C; HPLC: 99.4%.

Example 69

3- [2- (4-Diethylaminophenyl) -2-oxoethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

2-chloro-l- (4-diethylamino-phenyl) ethan-l-one.

NMR: ^{DMSO; H} δ (ppm): 1.15 (t, 6H); 3.30-3.50 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H); 5.35 (s. 2H);

6.9C (d, 2H); 7.30 (d, 2 H); 7.65 (d, IH); 7.90 (m, 1H); 8.60 (s, 1H); 9.25 (t, 1H).

(M, 4H); 3.60

6.75 (d, 2 H);

(D 2 H); 8.30

IR: 3370, 1670,

08 cm ^-1 ;

1655, 1596, 1504, 1258, 1242,

1190, mp = 237 ° C; HPLC: 97.0%.

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Example 70

Ethyl [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl acetate

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1 and ethyl 2-chloroacetate.

NMR: DMSO ^{Χ Η δ} (ppm): 1.20 (t, 3H), 3.60 (s, 3H); 3.70 (s, 3H);

4.15 (q, 2 H); 4.40 (d, 2 H); 4.70 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.60 (d, 1H); 8.30 (m, IH); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 1711, 1668, 1637, 1509, 1247, 1212, 1032, 835, 522 cm ^-1 ;

mp 170 ° C; TLC 97.7%.

Example 71

3- (2-Hydroxyethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

2-Bromo-ethanol-l-ol.

NMR: DMSO δ δ (ppm): 3.50-3.65 (s, 5H); 3.70 (s, 3H); 4.05 (t, 2 H); 4.40 (d, 2 H); 4.80 (t, 1H); 6.90 (d, 2 H); 7.25 (d, 2 H);

7.50 (s, 1H); 8.25 (m, IH); 8.60 (s, 1H); 9.25 (t, 1H).

IR: 3290, 1702, 1654, 1639, 1619, 1509, 1327, 1240,

1071, 835, 753 cm ^-1 ;

mp = 168 ° C; HPLC: 96.7%.

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Example 72

Methyl 3- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] propionate

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and methyl 3-bromopropanoate.

NMR: ^{DMSO; H} δ (ppm): 2.60 (t, 2H); 3.50 (s, 3H); 3.60 (s, 3H);

3.70 (s, 3H); 4.20 (t, 2H); 4.40 (d, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.50 (d, IH); 8.25 (dd, 1H); 8.60 (s, 1H); 9.25 (t, 1 H).

IR: 3411, 2361, 1704, 1656, 1644, 1618, 1508, 1478,

1328, 1244, 953, 766 cm ^-1 ;

mp = 154.8 ° C; HPLC: 95.1%.

Example 73

3- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] propionic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B but using the compound obtained in Example 72.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.25.

NMR: ^{DMSO; H} δ (ppm): 2.50 (t, 2H); 3.55 (s, 3H); 3.70 (s, 3H);

4.15 (t. 2H); 4.40 (d, 2 H); 6.85 (d, 2 H); 7.25 (d, 2 H); 7.50 (d, 1H); 8.25 (dd, IH); 8.55 (s, 1H); 9.15 (t, 1H); 12.3 (bs, 1H).

IR: 3395, 2353, 1701, 1656, 1639, 1508, 1478, 1244,

1040, 839, 799, 754 cm ^-1 ;

mp = 201.5 ° C; HPLC: 96.4%.

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Example 74

Ethyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] butyrate

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1 and ethyl 4-bromobutyrate.

NMR DMSO ^: H? (Ppm): 1.10 (t, 3H); 1.90 (q, 2 H);

3.55 (s, 3H); 3.70 (s, 3H); 4.00 (bs, 4H); 4.45 (d, 2 H); 7.25 (q, 2 H); 7.50 (d, IH); 8.20 (dd, 1H);

9.15 (t, 1 H).

2.30 (- t, 2H);

(D 2 H); 6.90

8.60 (s, 1 H);

IR: 3378, 2943, 1704, 1657, 1647, 1617, 1509,

1246, 1178, 1030, 751 cm ^-1 ;

1477, mp = 138.9 ° C; HPLC: 99.1%.

Example 75

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] butanoic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B but using the compound obtained in Example 74.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf - 0.50.

NMR: DMSO δ (ppm) : 1,80 (Q, 2H); 2.25 (T, 2H); 3.50 (with, 3H); 3.70 (s, 3H); 4,0 ( t, 2H); 4.40 ( N, 2H); 6, 90 (D, 2H) r 7.25 (D 2 H); 7.50 (D, 1H); 8.25 (dd, 1 H); 8, 60 (s, 1 H); 9.20 (T, 1H);

12.0 (bs, 1H).

IR: 3346, 1024, 835, 752 cm @ ^-1 ;

1691, 1651, 1637, 1512, 1234, 1248, 1178,

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135 mp 165.6 ° C; HPLC 99.1%.

Example 76

Methyl {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} acetate

The title compound was obtained following the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and methyl 4- (bromomethyl) phenylacetate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: DMSO ^{Χ Η δ} (ppm): 3.55 (s, 3H); 3.60 (s, 1H); 3.65 (s, 2 H);

3.70 (s, 3H); 4.40 (d, 2 H); 5.15 (s. 2H); 6.90 (d, 2 H); 7.10-7.35 (m, 6H); 7.55 (d, 1H); 8.25 (dd, 1H); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 3370, 2951, 1707, 1655, 1639, 1616, 1509, 1328, 1251, 1157, 1036, 766 cm @ ^-1 ;

mp = 173.2 ° C; HPLC: 99.0%.

Example 77 {4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} acetic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B but using the compound obtained in Example 76.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

DMSO ^{Χ Η δ} (ppm): 3.55 (s, 2H); 3.60 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H); 5.15 (s. 2H); 6.90 (d, 2 H); 7.10-7.35 (m, 6H); 7.55 (d, 1H); 8.25 (dd, 1H); 8.60 (s, 1H); 9.20 (t, 1H); 12.3 (bs, 1H).

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IR: 3378, 1706, 1653, 1640, 1616, 1508, 1330, 1249,

114 9, 1032, 823, 766 cm ^-1 ;

mp = 165 ° C; HPLC: 96.7%.

Example 78

3- (4-Dimethylcarbamoylmethylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained from the compound obtained in Example 77 which is transformed in situ into the acid chloride by treatment with oxalyl chloride and then treated with a 2M solution of dimethylamine in THF.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: ^{DMSO; H} δ (ppm): 2.80 (s, 3H); 3.0 (s. 3H);

3.60 (s, 2 H); 3.75 (s, 3H); 4.40 (d, 2 H); 5.15 (d, 2 H); 7.15 (d, 2 H); 7.25 (d, 4H); 7.55 (d, IH);

8.65 (s, 1 H); 9.20 (t, IH).

3.55 (s, 3H);

(S, 2H); 6.90

8.25 (d, 1H);

IR: 3308, 2926, 1706, 1665,

1250, 1133, 11036, 834 cm ^-1 ;

1640, 1504, 1474

1320, mp 183 ° C; HPLC 93.2,%.

Example 79

1-Methyl-2,4, dioxo-3 - [(E) -3- (pyridin-3-yl) allyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

3 - ((E) -3-chloro-propenyl) -pyridine.

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TLC: CH ₂ Cl ₂ / MeOH 90:10 R f = 0.63 NMR: DMSO ³ δ δ (Ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.40 (d, 2 H); 4, 75 (D 2 H); 6. 40 to 6.50 (m, 1 H); 6, 50 -6, 60 (d, 1 H); 6.90 (d, 2 H); 7.20 -7.35 (m, 3H) ); 7.55 (d, 1 H); 7.85 (D, H ); 8.25 (D, 1H); 8.40

(S, lH); 8.60 (d, 2 H); 9.20 (t, 1H).

IR: 3395, 1703, 1643, 1509, 1479, 1254, 761 cm @ ^-1 ;

mp = 200.0 ° C; HPLC: 98.7%.

Example 80

1-Methyl-2,4-dioxo-3 - [(E) -3- (pyridin-4-yl) allyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and 4 - ((E) -3-chloropropenyl) pyridine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.43.

^X H NMR DMSO δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H);

4.80 (d, 2 H); 6.55 (d, IH); 6.60-6.70 (m, 1H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.35 (d, 2 H); 7.55 (d, 1H); 8.25 (dd, 1H); 8.45 (d, 2 H); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 3395, 1704, 1643, 1509, 1479, 1332, 1254, 980,

65 cm ^-1 ;

mp = 241 ° C; HPLC: 98.1%.

Example 81

1-Methyl-2,4-dioxo-3- (4-sulfamoylbenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

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The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and 4-bromomethylbenzenesulfonamide.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.48.

DMSO δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.40 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.30 (s, 2 H);

7.55 (d, 1H); 7.75 (d, 2 H); 8.25 (d, 1H); 8.60 (d, 2 H); 5.20

7.50 (d, 2H);

(S, lH); 9.2 (t, 1 H).

IR: 3338, 1708, 1654, 1616, 1548, 1507, 1329, 1245,

1036, 825, 751 cm ^-1 ;

mp = 219.0 ° C; HPLC: 94.9%.

Example 82

3- (4-Methanesulfonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained following the procedure of steps 1-5 to 2-5 of Preparation B using 3- (4-methanesulfonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid. .

NMR: DMSO ^{Χ Η δ} (ppm): 3.20 (s, 3H); 3.55 (s, 3H); 3.70 (s, 3H);

4.40 (d, 2 H); 5.25 (s, 2 H); 6.90 (d, 2 H); 7.15 (d, 2 H); 7.50-7.60 (m, 3H); 7.85 (d, 2 H); 8.30 (dd, 1H); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3370, 1707, 1658, 1641, 1303, 1149, 783 cm ^-1 ;

mp = 210 ° C; HPLC: 97.9%.

Example 83

3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

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Step 1: methyl 3- (4-chlorosulfonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

3.2 ml (47.5 mmol) of chlorosulfonic acid are added to the round-bottomed moisture-proof flask with stirring. The mixture was cooled in an ice bath and 2.2 g (6.80 mmol) of the compound obtained in Step 1 of Preparation C was slowly added. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice-water. The precipitate is filtered and dried to give 1.8 g of the desired product.

NMR: DMSO ² H δ (ppm): 3.55 (s, 3H); 3.90 (s, 3H); 5.15 (s. 2H);

7.25 (m, 2 H); 7.50-7.60 (m, 3H); 8.25 (dd, 1H); 8.60 (s, 1H).

Step 2: methyl 3- (4-dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

To a stirred solution of 0.4 g (0.94 mmol) of the compound obtained in Step 1 above in 25 mL of dichloromethane was added 3.3 mL (66 mmol) of a 2M solution of dimethylamine in THF. After 1 hour, the reaction mixture was concentrated in vacuo. The residue is purified by chromatography on silica gel, eluting with dichloromethane / acetone: 98: 2, to give 0.370 g of the desired product (yield: 91%).

NMR: DMSO ¹ H δ (ppm): 2.6 (s, 6H); 3.6 (s. 3H); 3.9 (s. 3H); 5.25 (d, 2 H); 7.60 (m, 3 H); 7.70 (m, 2 H); 8.25 (dd, IH); 8.60 (s, 1 H).

Step 3: 3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in the previous Step 2.

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NMR: DMSO ^: H? (Ppm): 2.60 (s, 6H); 3.55 (s, 3H); 5.25 (s, 2 H); 7.60 (m, 3 H); 7.70 (m, 2 H); 8.25 (dd, IH); 8.60 (s, 1H); 13.20 (bs, 1H).

Step 4: 3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Example 1 but using 4-methoxybenzylamine. The title compound crystallizes in dichloromethane / ether.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.48.

NMR: DMSO δ (ppm): 2.55 (s, 6H); 3.55 (s, 3H); 3.70 (s, 3H);

4.40 (d, 2 H); 5,25 i (S, 2H); 6.90 (d, 2 H); 7.25 (D 2 H); 7.55-7.60 (m, 3H), 7.60-7.70 (M, 2H); 8.30 (D, 1H) ; 8.65 (s, 1 H); 9.20 (t, IH). IR: 1708, 1660 1618 1503, 1477, 1335, 1247, 1160,

952, 760, 718 cm ^-1 ;

mp 112 ° C; HPLC 94.8%.

Example 84

3- [4- (2-Dimethylaminoethylsulfamoyl) benzyl] -1-methyl-2,4-didxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained according to the procedure of steps 1 to 4 of Example 83 using (in step 2) N, N'-dimethylethylene.

The title compound crystallizes in dichloromethane / ether.

TLC CH ₂ Cl ₂ / MeOH 90:10 R f = 0.47.

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^X H NMR DMSO δ (ppm): 2.0-2.15 (m, 6H); 2.20-2.35 (m, 2 H); 2,752.85 (m, 2 H); 3.55 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H); 5.20 (s, 2H); 6.85 (d, 2 H); 7.25 (d, 2 H); 7.45-7.65 (m. 4H); 7.65-7.80 (m, 2 H); 8.25 (d, 1H); 8.60 (m, IH); 9.20 (m, IH).

IR: 1707, 1656, 1618, 1508, 1477, 1326, 1249,

1155 cm ^-1 ;

mp = 114 ° C; HPLC: 90.9%.

Example 85

1-Methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Step 1: methyl 1-methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained according to the procedure of steps 1 to 3 of example 83 using methylamine in step 2.

Step 2: 1-Methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

To a cooled solution of 0.2 g (0.5 mmol) of the compound obtained in Step 1 above in 10 mL of dichloroethane was added 3.2 mL (6.4 mmol) of a 2M solution of trimethyl aluminum in toluene and 0.875 g (6.4 mmol) of 4 -metoxybenzylamínu. The solution was stirred at room temperature overnight and then at 60 ° C for 24 hours. The solution is evaporated in vacuo and the residue is purified by chromatography on silica gel eluting with dichloromethane / ether to give 0.085 g (yield 32%) of the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

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NMR: DMSO δ (ppm): 2.40 (d, 3H); 3.55 (s, 3H); 3.70 (s, 3H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.85 (d, 2 H); 7.25 (d, 2 H); 7.40 (q, IH); 7.50 (d, 2 H); 7.60 (d, 1 H); 7.70 (d, 2 H); 8.25 (d, 1H);

8.65 (s, 1 H); 9.2 (t, 1 H).

IR: 3338, 1708, 1654, 1616, 1548, 1507, 1329, 1245,

1036, 825, 751 cm ^-1 ;

mp = 217.0 ° C; HPLC 95.0%.

Example 86

Methyl 3- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and methyl 3- (bromomethyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: DMSO ^{Τ Η δ} (ppm): 3.50 (s, 3H); 3.70 (s, 3H); 3.80 (s, 3H);

4.40 (d, 2 H); 5.2 (s. 2H); 6.80-6.90 (m, 2 H); 7.2-7.3 (m. 2H); 7.4-7.5 (m. 1H); 7.5-7.6 (m, IH); 7.6-7.7 (m, IH); 7.8-7.9 (m, 1H); 7.95 (s, 1H); 8.30 (d, IH); 8.60 (s, 1H); 9.2 (t, 1H).

IR: 3254, 1729, 1705, 1659, 1637, 1502, 1299, 1249, 74 cm @ ^-1 ;

mp = 193.5 ° C; HPLC: 100

Example 87

3- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

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The title compound was obtained according to the procedure for Step 2-4 of Preparation B using the compound of Example 86.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 4.45 (d, 2 H);

5.20 (s, 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.40-7.45 (m, 1 H); 7.57.65 (m, 2 H); 7.80 (d, IH); 7.95 (s, 1H); 8.20 (d, 1H); 8.60 (s, 1H); 9.2 (t, 1H); 12.95 (s, 1H).

IR: 3400, 3190, 1705, 1659, 1646, 1616, 1510, 1247,

1197, 750 cm ^-1 ;

mp = 182 ° C; HPLC 98.8%.

Example 88 (E) -Methyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dibydro-2H-quinazolin-3-yl] but-2-enoate

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and methyl 4-bromocrotonate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.75.

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 3.60 (s, 3H); 3.70 (s, 3H);

4.45 (d, IH); 4.75 (d, 2 H); 5.9 (d, 1H); 6.70-6.90 (m, 2H); 6.96.95 (m, 1H); 7.2-7.3 (m. 2H); 7.55 (d, IH); 8.25 (d, IH); 8.60 (s, 1 H); 9.2 (t, 1 H).

NMR: 3408, 1708, 1644, 1617, 1507, 1477, 1280, 1248, 1036,

65 cm ^-1 ;

mp = 107.9 ° C; HPLC: 96.2%.

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Example 89

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] but-2-enoic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound of Example 88.

TLC CH ₂ Cl ₂ / MeOH 90:10 R f = 0.50.

NMR DMSO ¹ H δ (ppm): 3.50 (s, 3H); 3.70 (s, 3H); 4.30 (d, 2 H); 4.70 (d, 2 H); 5.70-5.80 (m, 1H); 6.70-6.85 (m, IH); 6.90 (d, 2 H);

7.25 (d, 2 H); 7.50 (d, IH); 8.20-8.25 (m, IH); 8.60 (s, 1H); 9.2 (t, 1 H); 12.3 (bs, 1H).

IR: 3409, 1700, 1644, 1617, 1506, 1304, 1248, 767 cm @ ^-1 ;

mp 245.5 ° C; HPLC: 91.3%.

Example 90

Methyl 5- [6- (4-methoxybezylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] furan-2-carboxylate

The title compound is obtained by the procedure of Example 34, Step 2, but using the compound obtained in Example 34, Step 1, and methyl (chloromethyl) -2-furoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

^X H NMR DMSO δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 3.75 (s, 3H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.55 (d, IH); 6.85 (d, 2 H); 7.25 (m, 3H); 7.55 (d, 1H); 8.25 (d, 1H); 8.60 (s, 1H); 9.2 (t, 1H).

IR: 3249, 1711, 1664, 1636, 1503, 1446, 1299, 1250, 1148, 1023, 824, 765 cm ^-1 ;

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145 melting point = 195.5 ° C; HPLC: 99.2%.

Example 91

5- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] furan-2-carboxylic acid

The title compound is obtained by hydrolyzing the compound of Example 90 in the presence of K ₂ CO ₃ in dioxane / water.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.10

NMR: DMSO ^{Χ Η δ} (ppm): 3.55 5.20 (s, 2H); 6.50 (s, 1H);

(D 2 H); 7.55 (d, 1H); 8.25

13.05 (bs, 1H).

(s, 3H); 3.70 (S, 3H); 4.40 (S, 2H); 6, 90 (D 2 H); 7.10 (S, lH) ; 7.25 (D, 1H); 8.60 (s, 1 H); 9.2 (T, 1H);

IR: 1711, 1661, 1618, 1505, 1477, 1326, 1248, 1141,

1024, 969, 824, 787 cm ^-1 ;

mp = 198 ° C; HPLC 100.0%.

Example 92

Methyl 5- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3--ylmethyl] -thiophene-2-carboxylate

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 step 1 and methyl 5-bromomethylthiophene-2-carboxylate. This compound is obtained as described in J. Med. Chem. 1998, 41 (1), 7495.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.20.

NMR DMSO ^: H? (Ppm): 3.55 (s, 3H); 3.75 (s, 3H); 3.80 (s, 3H);

4.40 (d, 2 H); 5.30 (s, 2 H); 6.90 (d, 2 H); 7.15 (d, 1H), 7.25

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146 (d, 2 H); 7.55 (d, 1H); 7.60 (d, 1H); 8.25 (d, 1H); 8.60 (s, 1H);

9.2 (t, 1H).

IR: 3249, 1707, 1660, 1635, 1515, 1326, 1294, 1092,

1036, 625, 749 cm ^{@ -1} ;

mp = 200.5 ° C; HPLC 91.5%.

Example 93

5- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] thiophene-2-carboxylic acid

The title compound is obtained by hydrolyzing the compound of Example 92 in the presence of K ₂ CO ₃ in dioxane / water.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.25.

NMR DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H);

5.36 (s, 2 H); 6.90 (d, 2 H); 7.15 (d, 1H); 7.25 (d, 2 H); 7.55 (m. 2H); 8.25 (d, 1H); 8.65 (s, 1H); 9.2 (t, 1H); 13.0 (m, 1H).

IR spectrum: 3241, 1705, 1662, 1632, 1541, 1325, 1246, 1032, 921, 826, 783 cm ^-1 ;

mp = 198.5 ° C; HPLC: 92.2%.

Example 94

1-Methyl-3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34 step 2 but using the compound obtained in Example 34 a step 1

4-nitrobenzyl bromide.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.47.

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NMR DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H);

5.25 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.50-7.65 (m, 3H); 8.15 (d, 2H); 8.25 (d, IH); 8.65 (s, 1H); 9.2 (t, 1 H).

IR: 1706, 1661, 1618, 1513, 1477, 1345, 1248, 752-1.

cm, mp = 129.0 ° C; HPLC: 100%.

Example 95

3- (4-Aminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Example 94 (1 g; 2.1 mmol) was hydrogenated to Pd / C in dichloromethane / methanol 80:20 (v / v). After stirring under a hydrogen atmosphere for 2 h, the reaction mixture was filtered. The solvent is removed from the filtrate in vacuo and the crude product is precipitated from dichloromethane / ether to give 0.800 g of the desired compound (yield: 85.8%).

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.19.

NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.45 (d, 2 H);

4.90-5.05 (m, 4H); 6.45 (d, 2 H); 6.90 (d, 2 H); 7.05 (d, 2 H); 7.25 (d, 2 H); 7.50 (d, IH); 8.25 (d, 1H); 8.60 (s, 1H); 9.2 (t, 1H).

IR: 3387, 1701, 1647, 1615, 1511, 1478, 1245, 799 cm @ ^-1 ;

mp = 167 ° C; HPLC: 99.0%.

Example 96

3- (4-Dimethylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

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0.220 g (0.5 mmol) of the compound of Example 95 in 5 mL of CH ₃ CN was charged to a round moisture-protected flask and 0.150 g (5 mmol) of powdered paraformaldehyde, 0.695 g (1.5 mmol) of NaBi was added with stirring. ^ CN and 100 μΐ acetic acid. After 2 h at room temperature and reflux for 1.5 h, the reaction mixture was taken up in dichloromethane and washed with 1M NaOH solution. The organic phase is decanted, washed, dried and then concentrated in vacuo. The product is recrystallized from acetonitrile to give 0.130 g (yield: 55%) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.42.

NMR: DMSO ¹ H δ (ppm): 2.80 (s, 6H); 3.50 (s, 3H); 3.70 (s, 3H);

4.40 (d, 2 H); 5.00 (s. 2H); 6.60 (d, 2 H); 6.90 (d, 2 H); 7.15-7.25 (m, 4H); 7.50 (d, IH); 8.20 (d, IH); 8.60 (s, 1H); 9.2 (t, 1H).

IR: 1699, 1654, 1640, 1616, 1508, 1324, 1324 cm ^{@ -1} ;

mp = 205.0 ° C; HPLC: 98.9%.

Example 97

3- (4-Acetylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

To a round-bottomed flask protected from moisture was charged 0.190 g (0.43 mmol) of the compound of Example 95 in 10 mL of dichloromethane. Stir the solution and add 36 μΐ (40 mg, 0.51 mmol) of acetyl chloride and 72 μΐ of triethylamine. After 1 h at room temperature, 36 μΐ of acetyl chloride and 72 μΐ of triethylamine are added. After 1 h, the organic phase is washed with 1M HCl solution and dried and chromatographed on silica gel eluting with

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149 dichloromethane / ether to give 0.120 g (yield: 57%) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.17.

NMR: DMSO ¹ H δ (ppm): 2.0 (s, 3H); 3.55 (s, 3H); 3.70 (S, 3H); 4,4 0 (D 2 H); 5.05 (s, 2 H); 6.90 (d, 2 H); 7 , 20-7.30 (m, 4H) ); 7.45 (D, 2H) i; 7.50 (d, 1H); 9.25 (d, 1H); 8.60 (s, 1 H); 9.2 (T, 1H);

9.85 (s, 1 H).

IR: 3330, 1661, 1617, 1511, 1475, 1322, 1244, 825,

52 cm ^-1 ;

mp = 251.0 ° C; HPLC: 100.0%.

Example 98

3- [4- (N, N-Methylsulfonylamino) benzyl] -1-mesyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was prepared according to the procedure for EXAMPLE 97 using the compound obtained in Example 95 and methanesulfonyl chloride.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: DMSO ¹ H δ (ppm): 3.50 (s, 6H); 3.55 (s, 3H); 3.70 (s, 3H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.40-7.50 (m, 4H); 7.55 (d, 1H); 8.25 (d, IH); 8.65 (s, 1H); 9.2 (t, 1H).

IR: 1655, 1639, 1507, 1376, 1252, 1157, 905, 761 cm ^{@ -1} ;

mp = 198 ° C; HPLC: 100.0%.

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Example 99

3- (Benzofurazan-5-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained according to the procedure of Example 34 step 2 using the compound obtained in Example 34 step 1 and 5-bromomethylbenzofurazan.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

^X H NMR DMSO δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H);

5.25 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.60 (s, 1H); 8.0 (d, 1H); 8.25 (d, IH); 8.65 (s, 1H); 9.2

4.40 (d, 2 H);

(M, 2H); 7.90 (t, IH).

IR: 2370, 1701, 1653,

1181, 1028, 881, 781 cm ^-1 ;

1617, 1499

1477, 1326, 1243, mp = 140.5 ° C; HPLC: 100.0%.

Example 100

3- [2- (4-Fluorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained according to the procedure of step 2 of Example 34

using the compound obtained in step 1 of the example 34 and 4- -fluórfenoxyetylbromid. TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60. NMR: DMSO ^{Χ Η δ} (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.20 (D 2 H); 4.3-4.4 (m. 2H); 4.4-4.50 (m, 2 H); 6.80-7.0 (m, 4H); 7.0-7.1 (M, 2H); 7.2-7.30 (m, 2 H); 7.4-7.5 (M, 1H); 8.20-8.30 (m, 1 H);

8.66-8.70 (m, 1H); 9.2 (t, 1 H).

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IR: 1707, 1656, 1641, 1520, 1475, 1247, 1209, 1034,

828,725 cm ^-1 ;

mp = 159.6 ° C; HPLC: 99.7%.

Example 101

3- (2-Benzenesulfonylethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained according to the procedure of Example 34 step 2 using the compound obtained in Example 34 step 1 and 2-chloroethyl phenyl sulfone.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.55.

^X H DMSO δ (ppm): 3.50 (s, 3H); 3.6-3.70 (m, 2H); 3.75 (s, 3H); 4.3 (d, 2 H); 4.4-4.50 (m, 2 H); 6.90 (d, 2 H); 7.30 (d, 2 H); 7.4-7.7 (m. 4H); 7.9 (d. 2H); 8.20 (d, IH); 8.60 (s, 1H); 9.2 (t, 1H).

IR: 3274, 1708, 1663, 1638, 1514, 1499, 1249, 1147, 1034, 825, 746 cm ^{@ -1} ;

mp = 192.9 ° C; HPLC: 96.0%.

Example 102

3- (3-Fluoro-4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 34, Step 2, using the compound obtained in Example 34, Step 1, and

4-chloromethyl-2-fluoro-l-methoxybenzene.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

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NMR DMSO N δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 3.80 (s, 3H); 4.4 (d, 2 H); 5.10 (s. 2H); 6.90 (d, 2 H); 7.20 (m, 5H); 7.55 (d, 1H);

8.25 (d, 1H); 8.65 (s, 1 H); 9.2 (t, 1H).

IR: 3411, 2362, 1705, 1644, 1617, 1513, 1325, 1275,

1246, 1028, 827, 786 cm ^-1 ;

mp = 136 ° C; HPLC: 100.0%.

Example 103

1-Methyl-2,4-aioxo-3- [4- (2H-tetrazol-5-yl) benzyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

A solution of 3 g (6.6 mmol) of the compound of Example 60 in 100 ml of toluene, 1.3 g (19.8 mmol) of NaN ₃ and 2.72 g (19.8 mmol) of triethylamine hydrochloride was heated to 80 in an inert atmosphere. C. After 5 h, 10 mL of DMF is added and heating is continued overnight. After cooling, the precipitate was collected by filtration and washed successively with AcOEt, MeOH and 3N hydrochloric acid. The obtained solid was heated to boiling in AcOEt / MeOH and filtered and chromatographed on silica gel eluting with 10% NH ₄ OH in dimethylformamide to give 2 g of the desired compound (yield: 36%). TLC: CH ₂ Cl ₂ / MeOH 80:20

Rf = 0.30.

NMR DMSO N δ (ppm): 3.50 (bs, 1H); 3.55 (s, 3H); 3.70 (s, 3H); 4.4 (m. 2H); 5.20 (s, 2H); 6.90 (m, 2 H); 7.25 (m, 2 H); 7.50 (m. 3H); 8.0 (m. 2H); 8.3 (m, 1H); 8.70 (s, 1H); 9.2 (m, 1H);

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153 mp = 286 ° C; HPLC: 96.7%.

Example 104

1-Methyl-3- [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Step 2 of Example 34 using the compound obtained in Step 1 of Example 34 and 3- (4-chloromethyl-phenyl) -5-methyl- [1,2,4] oxadiazole, which was obtained in 4 steps of 4. -hydroxymetylbenzonitrilu.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.50.

NMR CDC1 ₃ ^{Τ Η δ} (ppm): 2.60 (s, 3H); 3.60 (s, 3H); 3.80 (s, 3H); 4.55 (m, 2 H); 5.25 (s, 2 H); 6.60 (s, 1H); 6.85 (m. 2H); 7.30 (m, 3H); 7.55 (m. 2H); 7.90 (m, 2 H); 8.3 (m, 1H); 8.50 (s, 1H);

mp = 235.0 ° C; HPLC: 95.1%.

Example 105

1-Methyl-3- [4- (3-methyl-1,2,4-oxadiazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Molecular sieves 4A, 5 ml are placed in a round-bottomed flask

DMF, 76 mg (1.02 mmol) of N-hydroxyacetamidine and 25 mg (1.02 mmol) of NaH. The mixture was stirred for 15 minutes and then 0.5 g (1.02 mmol) of the compound of Example 34 was added. The reaction mixture was heated at 65 ° C for 4 h and then filtered through diatomaceous earth. The filtrate is poured into 100 ml of water, the precipitate is filtered, washed successively with ethanol, water and ether to give 0.210 g (yield: 40%) of the title compound.

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TLC: CH ₂ Cl ₂ / MeOH SO: 5 Rf = 0.50.

NMR: DMSO δ (ppm): 3.3 (s, 3H); 3.55 (s, 3H); 3.70 (s, 3H);

4.40 (m, 2 H); 5.25 (s, 2 H); 6.90 (m, 2 H); 7.25 (m, 2 H); 7.55 (m, 3x4); 8.0 (d, 2 H); 8.3 (m, IH); 8.60 (s, 1H); 9.2 (m, 1H);

mp = 226.0 ° C; HPLC: 98.6%.

Example 106

Methyl 2-chloro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained following the procedure of Example 34, Step 2, using the compound obtained in Example 34, Step 1, and methyl 2-chloro-4-chloromethylbenzoate.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 3.80 (s, 3H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.90 (m, 2 H); 7.25 (m, 3H); 7.60 (d, 1H); 7.75 (d, IH); 7.95 (s, 1H); 8.3 (m, IH); 8.70 (s, 1H); 9.2 (m, IH);

m.p. = 229.0 C ^3; HPLC: 98.8%.

Example 107

2-Chloro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 106 with an aqueous solution of methanol and K 2 CO 3.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0,30-

DMSO Ή δ (ppm): 3.55 (s, 3H); 3.70 (S, 3H); 4.40 (m, 2H); 5.20 (S, 2H); 6. Δ5 (m, 2H); 7.20 (m, 3H); 7.60 (m, IH); 7.70 (m, 1H); 7.95 (n, 13 ); 8.3 (m, 1H) ); 8.60 (s, 1 H) ; 9.2 (m, 1K); 13.2 (s, 13Ϊ);

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155 mp = 216.0 ° C; HPLC: 96.5%.

Example 108

1-Methyl-3- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained according to the procedure of Example 34 step 2 using the compound obtained in Example 34 step 1 and 5- (4-chloromethylphenyl) -1-methyl-1H-tetrazole.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 4.10 (s, 3H).

4.40 (m, 2 H); 5.20 (s, 2H); 6.80 (d, 2 H); 7.25 (d, 2 H); 7.50 (m. 3H); 7.80 (m, 2 H); 8.2 (d, 1H); 8.60 (s, 1H); 9.2 (s, 1H);

mp = 143.0 ° C; HPLC 100%.

Example 109

1-Methyl-3- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

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The title compound is obtained according to the procedure of Example 34, Step 2, using the compound obtained in Example 34, Step 1, and 5- (4-chloromethylphenyl) -2-methyl-2H-tetrazole.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

^X H DMSO δ (ppm): 3.50 (s, 3H); 3.70 (s, 3H); 4.40 (m, 5H); 5.20 (s, 2H); 6.90 (m, 2 H); 7.25 (m, 2 H); 7.50 (m. 3H); 8.0 (m, 2K); 8.3 (d, IH); 8.60 (s, 1H); 9.2 (m, 1H);

mp = 226.0 ° C; HPLC: 98.2%.

Example 110

Methyl 2-methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained following the procedure of Example 34, Step 2, using the compound obtained in Example 34, Step 1, and methyl 4-bromomethyl-2-methoxybenzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

CDCl ₃ ² H δ (ppm): 3.60 (s, 3H); 3.80 (s, 3H); 3.85 (s, 3H); 3.90 (s, 3H); 4.55 (d, 2 H); 5.20 (s, 2H); 6.45 (m, IH); 6.80 (d, 2 H); 7.05 (d, IH); 7.20 (m, 4H); 7.7 C (d, 1H); 8.3 (d, 1H); 8.50 (s, 1 H);

mp = 170.0 ° C; HPLC: 98.6%.

Example 111

2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 110 using K ₂ CO ₃ in a mixture of methanol and water. After

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157 of the reaction mixture, the resulting precipitate is collected by filtration to give the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 3.80 (s, 3H);

4.40 (s, 2 H); 5.15 (s. 2H); 6.90 (m, 3H); 7.10 (s, 1 H); 7.30 (m, 2 H); 7.60 (m, 2 H); 8.3 (m, 1H); 8.60 (s, 1H); 9.2 (m, 1H); 12.5 (bs, 1H);

mp = 189 ° C; HPLC: 100.0%.

Example 112

Methyl 2-hydroxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

To a stirred solution of 1 g (1.93 mmol) of Example 111 in 15 mL of dichloromethane at 0 ° C was added, under an inert atmosphere 7.7 ml (7.7 mmol) BC1 ₃ M solution in dichloromethane. After stirring at 0 ° C for 15 min and at room temperature for 1 h, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase is dried and concentrated in vacuo. The precipitate obtained is purified by chromatography on silica gel, eluting with dichloromethane / methanol 99: 1, to give 0.460 g (yield: 47%) of the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

NMR: DMSO ^X H δ (ppm) : 3,50 (S, 3H); 3.70 (s, 3H); 3.85 (s, 3H); 4.40 (D 2 H); 5.10 (S, 2H); 6.85 (m. 4H); 7.25 (D 2 H); 7.55 (d, 1 H) ); 7.70 (D, lH); 8.3 (m, 1H); 8.60 (s, 1 H); 9.2 (M, 1H); 10.5

(s, 1 H);

mp = 205.0 ° C; HPLC: 100.0%.

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Example 113

2-Hydroxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dinydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 112 using K 2 CO 3 in a mixture of methanol and water. After acidification of the reaction mixture, the precipitate obtained is collected by filtration to obtain the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

NMR: DMSO ^{Χ Η δ} (ppm): 3.50 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H);

5.15 (s. 2H); 6.80 (m, 4H); 7.25 (m, 2H); 7.55 (m, IH); 7.70 (d, 1H); 8.3 (m, 1H); 8.60 (s, 1H); 9.2 (m, IH); 11.3 (bs, 1H); 13.8 (s, 1H);

mp = 262.0 ° C; TLC: 98.2%.

Example 114

Methyl 2-methyl-4- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained following the procedure of Example 34, Step 2, from the compound obtained in Example 34, Step 1, and methyl 4-bromomethyl-2-methylbenzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: DMSO ¹ H δ (ppm): 2.5 (s, 3H); 3.50 (s, 3H); 3.70 (s, 3H); 3.80 (s, 3H); 4.40 (s, 2 H); 5.10 (s. 2H); 6.90 (m, 2 H); 7.25 (m, 4H); 7.50 (d, IH); 7.70 (d, IH); 8.2 (m. 1H); 8.60 (s, 1H); 9.2 (s, 1 H);

mp = 167.0 ° C; HPLC: 100.0%.

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Example 115

2-Methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 114 by first treating K ₂ CO ₃ in a mixture of methanol and water and then LiOH at boiling for 2 days. After acidification of the reaction mixture, the precipitate obtained is collected by filtration to obtain the desired compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO ^{Χ Η δ} (ppm): 2.5 (s, 3H); 3.55 (s, 3H); 3.80 (s, 3H);

4.40 (d, 2 H); 5.10 (s. 2H); 6.80 (d, 2 H); 7.25-7.1 (m. 4H); 7.55 (m, 1H); 7.75 (m, IH); 8.2 (d, 1 H); 8.60 (s, 1H); 9.2 (t, 1H); 12.7 (s, 1 H);

mp = 179.0 ° C; HPLC: 95.6%.

Example 116 1-Methyl-2,4-dioxo-3- (pyridin-4-methyl) -1,2,3,4-tetrahydroquinazinecarboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide

Step 1: methyl 2,4-dioxo-1-methyl-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained according to the procedure of step 4 of example 15 using the compound obtained in step 2 of example 20.

Step 2: 2,4-Dioxo-1-methyl-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in the preceding Step 1.

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Step 3: 1-Methyl-2,4-dioxo-3- (pyridine-4-methyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide of

To a stirred solution of 0.2 g (0.65 mmol) of the compound obtained in step 2 above in 7 mL of dichloromethane was added 0.113 g (0.65 mmol) of EDCI; 0.680 g (0.65 mmol) of HOBT and 0.064 g (0.060 mL, 0.65 mmol) of 3,4-methylenedioxybenzylamine. After stirring at room temperature for 20 hours and usual work-up, 0.140 g (yield: 48%) of the desired product is obtained.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 4.40 (d, 2 H); 5.20 (s, 2H);

6.0 (s. 2H); 6.80-6.95 (m, 3H); 7.25-7.35 (m, 2 H); 7.55-7.60 (m, 1H); 8.25-8.35 (m, IH); 8.45-8.50 (m, 2 H); 8.65 (s, 1H); 9.20 (t, IH).

IR: 3265, 1707, 1663, 1618, 1501, 1490, 1254, 1037, 92 5 cm ^-1 ;

mp = 161.7 ° C; HPLC: 94.6%.

Example 117

1-Methyl-2,4-dioxo-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazinecarboxylic acid 4-methoxybenzylamide

The title compound is obtained by the procedure of Example 116 step 3 using the compound obtained in Example 116 step 2 a

4-methoxybenzylamine. The product is purified by silica gel chromatography to give 0.280 g (yield 25%) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

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NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H);

5.15 (s. 2H); 6.80 (d, 2 H); 7.2-7.3 (m. 4H); 7.55-7.60 (m, 1 H);

8.25-8.30 (m, IH); 8.45 (d, 2 H); 8.60 (s, 1H); 9.20 (m, IH).

IR: 3231, 1706, 1657, 1625, 1505, 1324, 1248, 1039,

827 cm ^-1 ;

mp 180.7 ° C; HPLC: 94.3%.

Example 118

1-Methyl-2,4-dioxo-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxybenzylamide

To a stirred solution of 0.280 g (0.67 mmol) of the compound of Example 117 in 20 mL of dichloromethane at 0 ° C under an inert atmosphere was added a solution of 1.7 g (0.63 mL, 6.7 mmol) of BBr ₃ in 2 mL of dichloromethane. . After stirring at room temperature for 20 min, the reaction mixture was poured into saturated NaHCO ₃ solution, decanted and extracted. The organic phase is dried and concentrated in vacuo to give 0.150 g (yield: 53.4%) of the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

^X H DMSO δ (ppm): 3.60 (s, 3H); 4.40 (d, 2 H); 5.20 (s, 2H); 6.70 (d, 2 H); 7.15 (d, 2 H); 7.3 (d, 2 H); 7.55-7.60 (m, 1H); 8.30 (d, 1H); 8.50 (d, 2 H); 8.65 (s, 1H); 9.20 (m, 1H); 9.30 (s, 1H).

IR: 3388, 1701, 1656, 1639, 1615, 1508, 1251, 830, 772, 751 cm &^lt; -1 &gt;;

mp = 137.7 ° C; HPLC: 91.1%.

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Example 119

Methyl 4- [6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

Step 1: benzyl 3- (4-methoxycarbonylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained according to the procedure of steps 1-5 to 2-5 of Preparation B, in step 1-5, 4-aminoisophthalic acid 1-benzyl ester-3-methyl ester and methyl 4-aminomethylbenzoate are used. The desired product is purified by boiling in methanol.

TLC CH ₂ Cl ₂ / MeOH 90: 5 R f = 0.65; HPLC: 97.0%.

NMR: ^{DMSO; H} δ (ppm): 3.8 (s, 3H); 5.10 (s 2H); 5.35 (s. 2H);

7.20-7.80 (m, 8H); 7.80-7.90 (m, 2 H); 8.20-8.30 (m, 1H); 8.50 (s, 1 H); 11.90 (s, 1 H).

Step 2: Benzyl 3- (4-methoxycarbonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained according to the procedure of Step 4 of Example 15 using the compound obtained in the preceding Step 1.

TLC: CH ₂ Cl ₂ / MeOH 90: Rf 0.65 5; HPLC: 97.0%.

NMR: ^{DMSO; H} δ (ppm) 3.60 (s, 3H); 3.80 (s, 3H); 5.20 (s, 2H);

5.35 (s. 2H); 7.30-7.60 (m, 8H); 7.80-7.90 (m, 2 H); 8.20-8.30 (m, 1H); 8.60 (s, 1H).

Step 3: 3- (4-Methoxycarbonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

To a stirred solution of 10.8 g (23.6 mmol) of the compound obtained in Step 2 above in 120 mL of dichloromethane and 80 mL

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163 g of methanol are added 3.2 g of Pd / C. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 h and then filtered through diatomaceous earth. The filtrate was concentrated in vacuo to give a first crop of crystals. The insoluble portion was extracted three times with methanol / water / saturated NaHCO 3 solution. The organic phase is separated and acidified to pH 1 with concentrated hydrochloric acid solution to give a second crop of the desired product. The two portions are then combined and dried under vacuum to give 6.9 g of the desired product (yield: 79%).

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.80 (s, 3H); 5.20 (s, 2H);

7.40 (dd, 2 H); 7.60 (dd, 1H); 7.90 (dd, 2 H); 8.30 (dd, 1H); 8.60 (s, 1H); 13.20 (bs, 1H).

HPLC> 97.0%.

Step 4: methyl 4- [6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 3 and 3-methoxybenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90/10

Rf = 0.70.

DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.70 (s, 3H); 3.80 (d, 2 H); 5.20 (s, 2H); 6.80 (d, 1H); 6.90 (m, 2 H);

7.45 (d, 2 H); 7.55 (d, 1H); 7.85 (d, 20); 8.25 (s, 1H); 9.25 (t, 1H).

(S, 3H); 4.45

7.25 (m, 1H);

(D, IH); 8.60

IR: 3435, 2361, 1716, 1703, 1666, 1617, 1498, 1455,

1282, 1125, 839, 749 cm ^-1 ;

mp = 199.0 ° C; HPLC 98.6%.

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Example 120

4- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound was obtained by hydrolyzing the compound of Example 119 using K ₂ CO ₃ in methanol / water at boiling for 9 hours. After acidification, the precipitate obtained is collected by filtration to give the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: DMSO ¹ H δ (ppm) 3.55 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H);

5.20 (s, 2H);

(d, 2H); 7.55

6.80 (d, 1H); 6.90 (m, 2 H); 7.25 (d, 1H); 7.85 (d, 2 H); 8.25 (d, IH);

(T, 1H); 7.45

8.65 (s, 1 H);

9.25 (t, 1H); 12.85 (bs, 1H).

IR: 3395, 2345, 1719, 1647, 1616, 1501, 1310, 1238,

1052, 839, 781, 751 coat of arms ¹ ;

mp = 279.0 ° C; HPLC: 97.4%.

Example 121

Methyl 4- [1-methyl-6- (4-methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Example 1 using the compound obtained in Step 119 of Example 119 and 4-methylthiobenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: DMSO ² H δ (ppm): 2.45 (s, 3H); 3.55 (s, 3H); 3.80 (s, 3H); 4.45 (d, 2 H); 5.20 (s, 2H); 7.20 (m, 4H); 7.45 (d, 2 H); 7.55 (s, 1H); 7.90 (d, 2 H); 8.25 (d, 1H); 8.60 (s, 1H); 9.20 (t, 1H).

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IR: 3395, 1708, 1656, 1641, 1508, 1479, 1330, 1280,

1254, 1117, 783, 749 cm ^-1 ;

mp 172 ° C; HPLC: 99.2%.

Example 122

4- [1-Methyl-6- (4-methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 121 using K 2 CO 3 in methanol / water at boiling for 48 hours. After acidification, the precipitate obtained is collected by filtration to give the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.35.

NMR: ^{DMSO; H} δ (ppm): 2.45 (s, 3H); 3.55 (s, 3H); 4.45 (d, 2 H);

5.20 (s, 2H); 7.25 (m, 4H); 7.40 (d, 2 H); 7.55 (d, IH); 7.85 (d, 2 H); 8.25 (d, IH); 8.60 (s, 1 H); 9.25 (t, 1 H); 12.85 (bs,

1H).

IR: 1705, 1656, 1642, 1616, 1479, 1330, 1247, 1101,

1020, 760, 751 cm ^{@ -1} ;

mp = 171 ° C; HPLC: 98.0%.

Example 123

Mety1-4- [l-methyl-2,4-dioxo-6- (4-carbamoyl-trifluoromethoxybenzyl) -1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Example 1 using the compound obtained in Step 119 of Example 119 and 4-trifluoromethoxybenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.35.

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NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.80 (s, 3H); 4.50 (d, 2 H);

5.20 (s, 2H); 7.30 (d, 2 H); 7.35-7.50 (m, 4H); 7.55 (d, 1H); 7.90 (d, 2 (3); 8.25 (d, 1H); 8.65 (s, 1H); 9.30 (t, 1H).

IR: 1712, 1656, 1639, 1506, 1274, 1156, 1104, 751 cm &^lt; -1 &gt;;

mp = 212 ° C; HPLC: 99.6%.

Example 124

Methyl 4- [6- (4-fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 3 and 4-fluorobenzylamine.

TLC: ΟΗ ₂ Ο1 ₂ / ΟΗθΟΗ 90: 5 Rf = 0.45.

NMR: DMSO ^: δ (ppm): 3.55 (s, 3H); 3.80 (s, 3H); 4.45 (d, 2 H);

5.20 (s, 2H); 7.10-7.20 (m, 2 H); 7.30-7.40 (m, 2 H); 7.40-7.50 (d, 2 H); 7.55 (d, IH); 7.85 (d, 2 H); 8.25 (d, IH); 8.65 (s, 1K);

9.25 (t, 1 H).

IR: 1709, 1657, 1618, 1499, 1264, 769, 749, 716 cm @ ^-1 ;

mp = 198 ° C; HPLC: 98.2%.

Example 125

4- [6- (4-Fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound was obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in Example 124.

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TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = about, 25th NMR: DMSO ^X H δ (Ppm) : 3, 55 (S, 3H); 4.45 (D 2 H); 5.20 (s, 2H); 7.10 ' -7.20 (m. 2H) ; 7 30-7, 40 (M, 2H); 7.45 (D 2 H); 7.55 (D, 1H); 7, 90 (D 2 H); 8 2 5 (d, 1 H) ); 8.65 (s, 1 H); 9.25 (T, 1H); 12.90

(bs, 1H).

IR: 3661, 2765, 1710, 1649, 1617, 1505, 1224, 829,

752 cm ^-1 ;

mp = 272 ° C; HPLC: 98.0%.

Example 126

Mety1-4- {6 - [(benzofurazan-5-ylmethyl) -carbamoyl] -1-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl} -benzoate

The title compound is obtained according to the procedure of Example 1 using the compound obtained in Step 3 of Example 119 and C-benzofurazan-5-ylmethylamine, which is obtained from 5-bromomethylbenzofurazan by first treating with sodium diformylamide in acetonitrile at 70 ° C overnight and then 2 hours. boiling with 5% HCl / ethanol.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.85 (s, 3H); 4.65 (d, 2 H); 5.25 (s, 2 H); 7.45 (D, 2H; I; 7.60 (d, 2 H); 7.90 (M, 3H); 8.00 (D, lH); 8.30 (d, 1H); 8.65 (S, 1H); 9.40 (t, 1 H). IR: 3257, 1731, 1702 1659 1619 1506 1419 1281 1109, 877, 769,751 cm ^-1 ;

mp = 234 ° C; HPLC: 98.6%.

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Example 127 - {6 - [(Benzofurazan-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid

The title compound was obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in Example 126. After acidification, the precipitate was collected by filtration.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.35.

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 4.60 (d, 2 H); 5,20 ( s, 2H); 7.40 (d, 2 H); 7, 60 (D 2 H); 7.85 (d. 3H); 8.00 (d, 1 H); 8.25 (d, 1 H); 8.65 (S, 1H) ; 9.40 (t, 1 H); 12.9 (bs, 1H). IR spectrum: 3249. 1708 1662 1617 1479 1427 1322, 1250 1008, 879, 790, 754 cm ^-1 ;

mp = 276 ° C; HPLC: 97.6%.

Example 128

Methyl 4- [6- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

Step 1: 4-Amino-isophthalic acid 3-methyl ester

The title compound was obtained according to the procedure of Step 119 of Example 119 using 4-amino-isophthalic acid 1-benzyl ester-3-methyl ester.

Step 2: 6-Amino-N- (4-methoxybenzyl) isophthalic acid methyl ester

The title compound is obtained by the procedure of Example 1 using the compound obtained in the previous step 1 and 4-methoxybenzylamine.

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Step 3: methyl 4- [6- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound is obtained according to the procedure of steps 1-5 to 2-5 of Preparation B using step 1-5 of the compound obtained in the previous step 2 and methyl 4-aminomethylbenzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.55.

NMR: ^{DMSO; H} δ (ppm): 3.70 (s, 3H); 3.80 (s, 3H); 4.40 (d, 2 H); 5.15 (s. 2H); 6.90 (d, 2 H); 7.20 (m, 3H); 7.45 (d, 2 H); 7.90 (d, 2 H); 8.15 (d, IH); 8.50 (s, 1H); 9.15 (t, 1H); 11.8 (s, 1H).

IR: 3265, 2935, 2553, 1719, 1665, 1637, 1514, 1459, 1275, 1105, 827, 751 cm @ ^-1 ;

mp = 287.5 ° C; HPLC: 98.3%.

Example 129

Methyl 4- [l-ethyl-6- (4-benzylcarbamoyl) -2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Step 4 of Example 15 using the compound obtained in Example 128 and iodomethane in DMF and K ₂ CO ₃ . The title compound crystallizes in dichloromethane / ether.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.55.

NMR: DMSO ^J H δ (ppm) : 1,25 (T, 3H); 3, 75 (s, 3H); . 3.85 (s, 3H); 4.20 (d, 2 H); 4,4 0 (D 2 H); 5.25 (S, 2H) ; 6.90 (D, 2H) ; 7.25 (d, 2H); 7.45 (D 2 H); 7.60 (D, 1H); 7, 90 (D 2 H); 8.25 (D, lH);

8.65 (s, 1 H); 9.20 (t, IH).

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IR: 3403, 2361, 1708, 1659, 1646, 1615, 1508, 1273,

1251, 1113, 847, 758 cm ^-1 ;

mp = 190 ° C; HPLC: 96.9%.

Example 130

4- [1-Ethyl-6- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

The title compound is obtained by hydrolyzing the compound of Example 112 using K 2 CO 3 in methanol / water at boiling for 3 hours. After acidification of the reaction mixture, the precipitate obtained is collected by filtration to obtain the desired product.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.45.

NMR: DMSO ^{Σ Η δ} (ppm): 1.25 (t, 3H); 3.70 (s, 3H); 4.20 (q, 2 H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.40 (d, 2 H); 7.60 (d, 1H); 7.85 (d, 2 H); 8.25 (d, 1H); 8.65 (s, 1H);

9.20 (t, 1H); 12.85 (bs, 1H).

IR: 2361, 1708, 1655, 1616, 1501, 1466, 1322, 1250,

1177, 1032, 823, 754 sense ¹ ;

mp = 160 ° C; HPLC: 98.2%.

Example 131 3- (4-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

Step 1: methyl 3- (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained by the procedure of Example 15, Step 4, using the compound obtained in the Example 16 step.

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Step 2: 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in the preceding Step 1.

Step 3: 3- (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound was obtained (0.160 g, yield: 63%) according to the procedure of step 3 of Example 116 using the compound obtained in the previous step 2 and 4- (aminomethyl) pyridine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.7 (s. 3H); 4.5 (d, 2 H); 5.10 (s. 2H); 6.80-6.90 (m, 2 H); 7.30-7.35 (m, 4H); 7.55-7.60 (m, 1 H);

8.25-8.30 (m, 1H); 8.38-8.42 (m, 2 H); 8.70 (s, 1H); 9.35 (t, 1H).

IR: 3269, 1705, 1659, 1644, 1615, 1510, 1245, 1180,

42.785 cm ^-1 ;

mp 213.9 ° C; HPLC: 97.8%.

Example 132 3- (4-Hydroxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

To a stirred solution of 0.630 g (1.46 mmol) of the compound of Example 131 in 50 mL of dichloromethane under an inert atmosphere was added a solution of 3.7 g (1.3 mL, 14.6 mmol) of BBr ₃ in 5 mL of dichloromethane. After stirring at room temperature for 1 h, the reaction mixture was cooled and poured into 100 mL of saturated NaHCO ₃ solution. The precipitate obtained is purified by chromatography on silica gel at

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TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO ⁷ H δ (ppm): 3.45 (s, 3H); 4.45 (d, 2 H); 5.0 (s. 2H); 6.60 (d, 2 H); 7.1 (d, 2 H); 7.25 (d, 2 H); 7.5 (d, 1 H); 8.20 (d, IH); 8.40 (d, 2 H); 8.60 (s, 1H); 9.20 (s, 1H); 9.20 (t, 1H).

IR: 3048, 1705, 1659, 1642, 1507, 1479, 1328, 1244, 831 cm &^lt; -1 &gt;;

mp = 262.0 ° C; HPLC: 94.8%.

Example 133 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

The title compound was obtained according to the procedure of Example 33 using the same substrate and 4-picolylamide (amidation).

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.25.

NMR DLys ³ Η δ (ppm): 3.45 (s, 3H); 4.5 (d, 2 H); 7.3 (d, 2 H); 7.55 (d, IH); 8.25 (d, 1 H), 8.5 (d, 2 H); 8.6 (s, 1H); 9.35 (t, 1H); 11.7 (s, 1 H).

IC spectrum: 3185, 1686, 1618, 1479, 1417, 1326, 782 cm ^-1 ;

mp = 292 ° C HPLC: 96.4%.

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Step 2: 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound is obtained according to the procedure of step 2 of Example 34 using the compound obtained in the preceding step 1 and α-bromo-β-tolunitrile.

TLC: AcOEt R f = 0.55.

NMR CDCl ₃ ¹ H δ (ppm): 3.60 (s, 3H); 4.60 (d, 2 H); 5.30 (s, 2 H); 7.3 (m. 3H); 7.60 (s, 4 H); 8.40 (m, IH); 8.45 (m. 2H); 8.65 (m, 1H); 8.80 (s, 1H);

mp = 258 ° C; HPLC 98.9%.

Example 134 1-Methyl-2,4-dioxo-3- (3-pyridin-4-ylalyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound was obtained according to the procedure of Example 34, Step 2, using the compound obtained in Example 133, Step 1, and 4- (3-chloropropenyl) pyridine hydrochloride.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO ¹ H δ (ppm): 3.60 (s, 3H); 4.50 (m, 2 H); 4.80 (m, 2 H); 6.50 (m, IH); 6.65 (m, 1H); 7.3 (m. 2H); 7.40 (m, 2 H); 7.60 (d, 1H); 8.25 (d, 1H); 8.50 (m, 4H); 8.65 (s, 1H); 9.35 (m, IH);

mp 117 ° C; HPLC: 99.5%.

Example 135

Methyl 4- {1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate

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The title compound is obtained according to the procedure of Example 34, Step 2, using the compound obtained in Example 133, Step 1, and methyl 4- (bromomethyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.45.

NMR: DMSO δ (ppm): 3.55 (s, 3H); 3.80 (s, 3H); 4.5 (d, 2 H);

5.20 (s, 2H); 7.3 (m. 2H); 7.45 (d, 2 H); 7.60 (d, 1H); 7.90 (m, 2 H); 8.25 (d, IH); 8.5 (m. 2H); 8.65 (s, 1H); 9.35 (t, 1H).

IR 3265, 1718, 1704, 1663, 1641, 1318, 1289, 1113, 751 cm &^lt; -1 &gt;;

mp = 236 ° C; HPLC: 97.5%.

Example 136

- {1-Methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) -carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl [benzoic acid

The title compound was obtained following the procedure of Step 2-4 of Preparation B using the compound obtained in Example 135. The corresponding hydrochloride was obtained by dissolving the compound in hot isopropanol / 0.1M HCl. The desired compound is purified by crystallization from acetonitrile.

NMR: DMSO H (t, 2H); 5.20

8.30 (d, IH);

δ (ppm): 2.4-4.40 (s, 2H); 7.40 (d, 2 H)

8.70 (s, 1H); 8.80 (m, 1H); 3.60

7.60 (d, IH);

(D, lH); 9.65 (s, 3H); 4.15

7.90 (m, 4H), (t, 1H); 12.9 (bs, 1H).

IR spectrum:

3265, 1718, 1704,

1663 1641 1318

1289, 1113, cm melting point = 268 ° C; HPLC: 97.9

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Example 137

Methyl (4- {1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} phenyl) acetate

The title compound is obtained by the procedure of Example 34, Step 2, using the compound obtained in Example 133, Step 1, and methyl 4- (bromomethylphenyl) acetate.

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.45.

NMR: DMSO ^{Τ Η} 8 (ppm): 3.50-3.60 (s, 6H); 3.65 (s, 2 H); 4.5 (t, 2 H); 5.15 (s. 2H); 7.20 (m, 2 H); 7.20-7.35 (m, 4H); 7.55 (d, IH); 8.25 (d, 1H); 8.5 (d, 2H) -8.65 (s, 1H); 9.35 (t, 1H).

IR: 3298, 1736, 1707, 1663, 1631, 1505, 1473, 1320, 1157, 751 cm @ ^-1 ;

mp = 141 ° C; HPLC: 96.4%.

Example 138 (4- (1-Methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} phenyl) acetic acid

The title compound was obtained following the procedure of Step 2-4 of Preparation B using the compound obtained in Example 137. The corresponding hydrochloride was obtained by dissolving the compound in hot isopropanol / 0.1M HCl. The desired compound is purified by crystallization from acetonitrile.

NMR: ^{DMSO; H} δ (ppm): 2.50 to 5.50 (br s, OH + HC1); 3.45-3.60 (2s, 5H); 4.70 (d, 2 H); 5.15 (s. 2H); 7.15 (d, 2 H); 7.25 (d, 2 H);

7.55 (d, 1H); 7.85 (d, 2 H); 8.30 (d, IH); 8.65 (s, 1H); 8.75 (d, 2 H); 9.55 (t, 1 H).

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IR: 3298, 1736, 1707, 1663, 1631, 1505, 1473, 1320,

1157,751 cm ¹ ;

mp = 241 ° C; HPLC: 97.5%.

Example 139

4- {l-methyl-2,4-dioxo-6 - [(1-oxy-pyridin-4-ylmethyl) -carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} -benzoate

To a stirred suspension of 0.500 g (1.10 mmol) of the compound of Example 135 in 20 mL of dichloromethane at -20 ° C was added a solution of 0.250 g (1.10 mmol) of meta-chloroperbenzoic acid in 5 mL of dichloromethane. The mixture was stirred at room temperature overnight with saturated Na ₂ CO ₃ solution and water. and concentrated in vacuo, the residue purified by chromatography on silica gel eluting with a gradient of methanol in dichloromethane. The product is precipitated in dichloromethane / ether to give 0.300 g (yield: 57%) of the title compound.

then washed sequentially The organic phase is dried

TLC: CH ₂ Cl ₂ / MeOH 90:10, Rf = 0.28.

NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 3.85 (s, 3H); 4.45 (d, 2 H); 5.25 (s, 2 H); 7.3 (d, 2 H); 7.45 (d, 2 H); 7.60 (d, 1H); 7.90 (d, 2 H); 8.15 (d, 2 H); 3.30 (s, 1H); 8.65 (s, 1H); 9.35 (t, 1H).

IR: 1705, 1655, 1617, 1478, 1283, 750, 711 cm ^x;

mp = 218 ° C; HPLC: 99.1%.

Example 140

4- {i-Methyl-2,4-dioxo-6 - ((1-oxypyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid

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The title compound was obtained according to the procedure of Step 2-4 of Preparation 13 using the compound obtained in Example 139.

NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 4.55 (d, 2 H); 5.20 (s, 2H);

7.30-7.50 (m, 4H); 7.60 (d, 1 H) 7.85 (d, 2 H); 8.25 (d, 2 H); 8.30 (d, 1H); 8.65 (s, 1H); 9.35 (t, 1H); 12.9 (bs, 1H).

IR: 1702, 1655, 1617, 1479, 1245, 753 cm @ ^-1 ;

mp = 192 ° C; HPLC: 98.4%.

Example 141

Methyl {6 - [(1,3-benzodioxol-5-ylmethyl) -carbamoyl] -3-benzy1-2,4-dioxo-4-dihydro-2H-quinazolin-l-yl} acetate

The title compound is obtained by alkylating the compound of Example 3 using K 2 CO 3 and methyl bromoacetate in DMF.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: DMSO ¹ H δ (ppm): 3.70 (s, 3H); 4.40 (d, 2 H); 5.05 (s, 2 H); 5.15 (s. 2H); 6.0 (s. 2H); 6.85 (m. 3H); 7.30 (m, 5H); 7.55 (d, 1H); 8.20 (d, IH); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 3282, 2361, 1736, 1669, 1632, 1464, 1370, 1236, 1040, 833, 776, 758 cm @ ^-1 ;

mp = 194.0 ° C; HPLC: 97.6%.

Example 142 [6 - [(1,3-Benzodioxol-5-ylmethyl) carbamoyl] -3-benzyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl} acetic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in Example 141.

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TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: DMSO ¹ H δ (ppm): 4.35 (d, 2K); 4.90 (s, 2 H); 5.15 (s. 2H); 5.95 (s, 2 H); 6.80 (m, 3 H); 7.30 (m, 5H); 7.50 (d, 1H); 8.20 (d, 1H); 8.60 (s, 1H); 9.20 (t, 1H); 13.25 (bs, 1H).

IR: 3346, 2935, 1709, 1668, 1612, 1499, 1467, 1305,

1250, 1117, 1036, 873 cm ^-1 ;

mp = 163.0 ° C; HPLC 99.6%.

Example 143

4- {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl [-benzoate

The title compound was obtained according to the procedure of Step 2 of Example 34 using the compound obtained in Example 37 and methyl 4- (bromomethyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.90 (s, 3H); 4.40 (d, 2 H);

5.20 (s, 2H); 6.0 (s. 2H); 6.80-6.95 (m, 3H); 7.45 (d, 2 H); 7.60 (d, 1H); 7.85 (d, 2 H); 8.30 (d, 1H); 8.65 (s, 1H); 9.20 (t, 1H).

IR: 3418, 1713, 1666, 1657, 1617, 1497, 1477, 1280, 1252, 1038, 770, 749 cm @ ^-1 ;

mp = 233.5 ° C; HPLC: 99.6%.

Example 144 - {6 - [(1,5-Benzodioxol-S-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid

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The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound obtained in Example 143.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: ^{DMSO; H} δ (ppm) 3.60 (s, 3H); 4.40 (d, 2 H); 5.20 (s, 2H).

5.95 (s, 2 H); 6.70-6.95 (m, 3H); 7.40 (d, 2 H); 7.60 (d, IH); 7.85 (d, 2 H); 8.30 (d, IH); 8.60 (s, 1H); 9.20 (t, IH); 12.85 (s, 1H).

IR: 3377, 3233, 1717, 1698, 1665, 1649, 1502, 1481,

1236,751 cm ¹ ;

mp = 295.7 ° C; HPLC: 97.9%.

Example 145

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-sulfamoyl-benzylamide

The title compound was prepared according to the procedure of Example 9 using the compound obtained in Preparation C and 4- (aminomethyl) benzenesulfonamide hydrochloride hydrate.

TLC: _CH2 C1 ₂ / MeOH 90:10, Rf = 0.37.

NMR: DMSO ¹ H δ (ppm): 3.60 (s, 3H); 4.55 (d, 2 H); 5.15 (s. 2H);

7.2-7.35 (m. 7H); 7.50 (d, 2 H); 7.60 (d, IH); 7.80 (d, 2 H); 8.30 (d, 1H); 8.65 (s, 1H); 9.35 (t, 1H).

IR 3290, 1709, 1652, 1618, 1503, 1321, 1154, 702 cm ^-1 ;

mp = 266 ° C; HPLC: 97.5%.

Example 146 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quazoline-6-carboxylic acid [3- (pyridin-4-ylsulfanyl) -propyl] -amide

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180

The title compound was obtained according to the procedure of Example 9 using the compound obtained in the preparation of C, 3- (pyrydin-4-ylsulfanyl) propylamine and dichloromethane as solvent. 3- (Pyridin-4-ylsulfamyl) propylamine was obtained as described above

in the publication Bioorg. Med. Chem. 1996 4, pp. 557-562. TLC: CH ₂ Cl ₂ / Ms eOH 90:10 Rf = 0.70. NMR: DMSO ² Η δ (ppm): 1 8-1.90 (m. 2H); 3.1 to 3.20 (M, 2H); 3,4- 3.50 (M, 2H); 3.60 (s, 3H);  5.20 (s, 2H) ; 7.2 to 7.40 (M, 7 H); 7,50- 7.55 (m, 1 H); 8.20 (d, 1H) ; 8.30 to 8.40 (M, 2H); 8.60 (s, IH); 8, 80 (T, 1H). IR spectrum: 3308, 1705, 1662.1636, 1578 1509 1447, 1321

04.712 cm ^-1 ;

mp = 130.7 ° C; HPLC: 99.2%.

Example 147 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-morpholin-4-yl-butyl) -amide

The title compound was obtained according to the procedure of Step 3 of Example 116 using the compound obtained in the preparation of C, 4-morpholin-4-yl-butylamine and dichloromethane as solvent. 4-Morpholin-4-yl-butylamine is obtained as described in J. Med. Chem. 1997, 40,

3915-3925.

TLC: CH ₂ Cl ₂ / MeOH 90:10 Rf = 0.60. NMR: DMSO ^λ Η δ (ppm): 1,4- -1.60 (m, 4H); 2.2-2.35 (M, 6H); 3, 20- 3.35 (M, 2H); 3 55 (s. 3H); 3.5-3.60 (m, 4H); 5,2 0 (with (2H); 7,2- 7.35 (m, 5H); 7 50 (d, 1H); 8.20-8.25 (m, IH); 3.60 (with (1H); 8, 70

(T, 1 H)

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IR: 3402, 2942, 1707, 1645, 1476, 1327, 1118, 763 cm @ ^-1 ;

mp = 170.6 ° C; HPLC: 99.3%.

Example 148 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-benzylpiperidin-4-yl) amide

The title compound was obtained according to the procedure of Example 9 using the compound obtained in the preparation of C, 4-amino-1-benzylpiperidine and dichloromethane as solvent. The title compound is crystallized from a mixture of dichloromethane and ether.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO ¹ H δ (ppm): 1.60 (m, 2H); 1.75 (m, 2 H); 2.0 (t, 2 H); 2.8 (d, 2 H); 3.45 (s, 2 H); 3.55 (s, 3H); 3.75 (m, IH); 5.15 (s. 2H);

7.30 (m, 10H); 7.55 (d, 1H); 8.20 (d, 1H); 8.50 (d, 1H); 8.60 (s, 1H).

IR: 3257, 2943, 2749, 1709, 1656, 1633, 1511, 1332,

1242, 1077, 829, 750 cm ^-1 ;

mp = 219.4 ° C; HPLC: 98.6%.

Example 149

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxybenzylamide

1.9 g (4.4 mmol) of the compound of Example 13 in 200 ml of dichloromethane are placed in an inert atmosphere round-bottomed flask. To the stirred solution was added dropwise 4.2 mL (11.1 g, 44 mmol) of BBr ₃ in 17 mL of dichloromethane. After

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The reaction mixture was poured into 500 mL of saturated NaHCO ₃ solution for 182 min at room temperature, extracted with dichloromethane, dried and concentrated in vacuo. Crystallization of the crude product in methanol / ether gave 1.35 g (yield: 74%) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.55.

NMR: ^{DMSO; H} δ (ppm) 3.60 (s, 3H); 4.40 (d, 2 H); 5.20 (s, 2H);

6.7-6.75 (m. 2H); 7.10-7.20 (m, 2 H); 7.2-7.40 (m, 5H); 7.55 (d, IH); 8.25 (d, IH); 8.65 (s, 1H); 9.20 (t, 1H); 9.0-9.3 (bs, 1H).

IR: 3314, 1698, 1635, 1622, 1500, 1480, 1453, 1255,

826, 748 cm ^-1 ;

mp = 191.8 ° C; HPLC: 96.4%.

Example 150

Ethyl (4 - {[(3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonyl) amino] methyl} phenoxy) acetate

0.45 g (1.08 mmol) of the compound of Example 149 in 13.5 ml of DMF was charged to a moisture-protected round-bottom flask. To the stirred solution was added 0.3 g of K ₂ CO ₃ (2.16 mmol) and 0.24 mL (2.016 mmol) of ethyl bromoacetate. After at 60 ° C, the reaction mixture is concentrated in vacuo, the crude product is taken up in dichloromethane, washed with water, dried and concentrated by evaporation.

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183 under vacuum to give 0.410 g (75.8% yield) of the title compound.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: ^{DMSO; H} δ (ppm): 1.2 (t, 3H); 3.60 (s, 3H); 4.15 (q, 2 H);

4.45 (d, 2 H); 4.80 (s, 2 H); 5.20 (s, 2H); 6.90 (d, 2 H); 7.2-7.40 (m, 7H); 7.5 (d, 1 H); 8.20 (d, IH); 8.60 (s, 1H); 9.20 (t, 1H).

IR: 3407, 1755, 1705, 1642, 1508, 1324, 1210, 750 cm ^{@ -1} ;

mp = 172.6 ° C; HPLC: 97.8%.

Example 151 (4 - {[(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonyl) amino] methyl} phenoxy) acetic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound of Example 150.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: DMSO δ (ppm): 3.60 (s, 3H); 4.40 (d, 2 H); 4.65 (s, 2 H);

5.15 (s. 2H); 6.85 (d, 2 H); 7.2-7.40 (m, 7H); 7.55 (d, 1H); 8.25 (d, 1H); 8.65 (s, 1H); 9.20 (t, 1H); 12.95 (bs, 1H).

IR: 3407, 1755, 1705, 1642, 1508, 1324, 1210, 750 cm ^{@ -1} ;

mp = 195.6 ° C; HPLC 98.3%.

Example 152

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-dimethylcarbamoylmethoxybenzylamide

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The title compound was prepared according to the procedure of Example 1 using the compound of Example 151 and a 2M solution of dimethylamine in THF.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: DMSO δ (ppm): 2.80 (s, 3H); 3.0 (s. 3H); 3.55 (s, 3H);

4.40 (d, 2 H); 4.80 (s, 2 H); 5.20 (s, 2H); 6.90 (d, 2 H); 7.2-7.40 (m, 7H); 7.50 (d, 1H); 9.20 (d, 1H); 8.65 (s, 1H); 9.25 (t, 1H).

IR: 3276, 1704, 1659, 1635, 1499, 1317, 1240, 1066,

50 cm ^-1 ;

mp 152.7 ° C; HPLC: 96.5%.

Example 153 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (3-phenylalyl) amide

The title compound was prepared according to the procedure for EXAMPLE 9 using the compound of Preparation C and 3-phenylalylamine hydrochloride.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: DMSO ¹ H δ (ppm): 3.55 (s, 3H); 4.10 (m. 2H); 5.20 (s, 2H); 6.35 (m, 1H); 6.60 (m, 1H); 7.20-7.35 (m, 8H); 7.40 (m, 2 H); 7.55 (d, 1H); 8.30 (d, 1H); 8.70 (s, 1H); 9.00 (m, 1H);

mp = 193.0 ° C; HPLC: 99.7%.

Example 154

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid 4-cyanobenzylamide

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The title compound was prepared according to the procedure of Example 9 using the compound of Preparation C and 4-aminobenzylbenzonitrile. The desired product is precipitated from dichloromethane / ether.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.46.

NMR: DMSO ¹ H δ (ppm) 3.55 (s, 3H); 4.60 (d, 2 H); 5.15 (s. 2H); 7.20-7.40 (m, 5H); 7.45-7.60 (m, 3H); 7.80 (d, 2 H); 8.25 (d, IH); 8.65 (s, 1 H); 9.40 (t, 1 H).

IR: 3305, 2224, 1708, 1664, 1638, 1507, 1318, 751 cm @ ^-1 ;

mp - 245.0 ° C; HPLC: 96.2%.

Example 155

4 - {[(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-β-carbonyl) amino] methyl} benzoic acid

The title compound is obtained according to the procedure of Step 2-4 of Preparation B using the compound of Example 11.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.30.

NMR: ^DMSO: Η δ (ppm): 3.55 (s, 3H); 4.55 (d, 2 H); 5.15 (s. 2H);

7.25 (m, 5H); 7.40 (d, 2 H); 7.55 (d, IH); 7.90 (d, 2H); 8.25 (d, 1H); 8.65 (s, 1H); 9.30 (t, 1H); 12.90 (bs, 1H).

IR: 3395, 1707, 1698, 1642, 1618, 1501, 1431, 1291,

1242, 938, 829, 759 cm ^-1 ;

mp - 228.5 ° C; HPLC: 96.9%.

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Example 156

3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-dimethylcarbamoyl-benzylamide

The title compound was prepared according to the procedure of Example 1 using the compound of Example 155 and a 2M solution of dimethylamine in THF.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70.

NMR: DMSO 1 H δ (ppm): 3.0 (m, 6H); 3.55 (s, 3H); 4.55 (d, 2 H);

5.15 (s. 2H); 7.30 (m, 9H); 7.60 (d, IH); 8.30 (d, 1H); 8.65 (s, 1 H); 9, 30 (t, 1 H).

IR: 3249, 2361, 1705, 1657, 1609, 1504, 1452, 1254,

1069, 1020, 839, 750 cm ^-1 ;

mp = 194.7 ° C; HPLC: 96.8%.

Example 157

3- (4-Dimethylaminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained following the procedure of steps 1-5 to 3-5 of Preparation B using (in step 1-5) 4-dimethylaminobenzylisocyanate and then the procedure of Example 1 using the compound obtained in the preceding step and 4-methoxybenzylamine.

NMR: DMSO δ (ppm): 2.80 (s, 6H); 3.70 (s, 3H); 4.40 (d, 2 H);

4.95 (s, 2 H); 6.60 (d, 2 H); 6.85 (d, 2 H); 7.15-7.25 (m, 5H); 8.10 (dd, IH); 8.50 (s, 1H); 9.10 (t, 1 H); 11.7 (s, 1H).

IR: 3177, 1729, 1630, 1512, 1445, 1249.765 cm ^-1;

mp = 267 ° C; HPLC: 98.5%.

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Example 158

3- [4- (N-Methylsulfonylamino) -benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was prepared according to the procedure for EXAMPLE 97 using the compound obtained in Example 95 and 2.5 equivalents of methanesulfonyl chloride.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.22.

NMR: DMSO ^{Χ Η δ} (ppm) 2.90 (s, 3H)

4.40 (d, 2 H); 5.10 (s. 2H); 6.90 (d, 2 H); 7.30 (d, 2 H); 7.55 (s, 1H)

9.2 (t, 1H); 9.70 (s, 1H).

3.55 (s, 3H); 3.70 (s, 3H);

(D 2 H); 7.10 (d, 2 H); 7.25

8.25 (d, 1H); 8.60 (s, 1H);

IR: 1655, 1615, 1513, 1500, 1325, 1248, 1148 cm @ ^-1 ;

mp = 224 ° C; HPLC: 98.8%.

Example 159 t-Butyl {5- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] pyridin-2-yl} carbamate

The title compound is obtained according to the procedure of Example 34 step 2 using the compound obtained in Example 34 step 1 and t-butyl (5-bromomethylpyridin-2-yl) carbamate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

^X H NMR DMSO δ (ppm): 1.45 (s, 9H); 3.55 (s, 3H); 3.75 (s, 3H);

4.40 (d, 2 H); 5.10 (s. 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 1H); 7.70 (m, 2 H); 8.25-8.30 (m, 2 H); 8.65 (s, 1H); 9.2 (t, 1 H); 9.70 (s, IH).

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IR: 1711, 1654, 1614, 1508, 1478, 1302, 1243,

1159 cm ¹ ;

mp = 204 ° C; HPLC: 99.3%.

Example 160

3- (6-Amino-pyridin-3-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound is obtained by deprotecting Example 159 using trifluoroacetic acid in dichloromethane.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: ^{DMSO; H} δ (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.40 (d, 2 H);

4.95 (s, 2 H); 5.80 (bs, 2H); 6.35 (d, IH); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.40 (dd, IH); 7.50 (d, IH); 7.95 (s, 1H); 8.25 (dd, IH); 8.60 (s, 1 H); 9.2 (t, 1 H).

IR: 1704, 1648, 1615, 1509, 1477, 1245 cm ^{@ -1} ;

mp = 155 ° C; HPLC: 99.5.

Example 161 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

Me

N ^ .0

Me

ABOUT

ABOUT

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189

Step 1: 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid

This compound is obtained by hydrolyzing ethyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylate in dioxane / water (Heterocycles 1998, 48). (12), 25212528) in the presence of LiOH.

TLC: CH ₂ Cl ₂ / M _e OH 90/10 Rf = 0.10.

NMR: ^{DMSO; H} δ (ppm): 3.30 (s, 3H); 3.60 (s, 3H); 8.70 (s, 1H);

9.15 (s, 1 H); 13.5 (bs, 1H).

Step 2: 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

The title compound was obtained according to the procedure of Example I using the compound obtained in the previous step 1 and piperonylamine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.90.

NMR: DMSO-d6 (ppm): 3.35 (s, 3H); 3.6 (s. 3H); 4.40 (d, 2 H); 6.0 (s. 2H); (M, 2H); 6.90 (s, 1H); 8.80 (s, 1H); 9.15 (s, 1H); 9.30 (t, 1H).

IR: 3227, 1705, 1663, 1632, 1608, 1498, 1299, 1250,

104 0.77 cm @ ^-1 ;

mp 218.4 ° C; HPLC: 94.6%.

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190

Example 162 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

Step 1: 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid

Said compound is obtained by hydrolysis of methyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylate (Heterocycles 1994, 37 (1), 563) -570) in dioxane / water in the presence of LiOH.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.01.

NMR: DMSO δ (ppm): 3.30 (s, 3H); 3.60 (s, 3H); 8.40 (s, 1H);

9.00 (s, 1 H); 13.3 (bs, 1H).

Step 2: 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 1 and piperonylamine.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.90.

4MR: DMSO δ (ppm): 3.35 (s, 3H);

6.0 (s. 2H); 6.80-6.90 (m, 2H); 6.95 (s, 1H); 9.25 (t, 1 H).

NMR

6.0

3.65 (s, 3H); 4.45 (d, 2 H);

(s, 1 H); 8.50 (s, 1 H); 8, 95

IR: 3379, 1713, 1662, 1478,

1253, 1238, 924, 750 cm ^-1 ;

mp = 288.7 ° C; HPLC: 96.3%.

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Example 163 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

Step 1: N '- (1-Benzyl-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl) -N, N-dimethylformamidine

A mixture of 0.56 g (2.5 mmol) of 6-amino-3-benzyl-1H-pyrimidine-2,4-dione (Tetrahedron Letters 1991, 32 (45), 6534-6540) and 20 ml

The DMF is stirred under an inert atmosphere. 1 ml (7.5 mmol) of N, N'-dimethylformamide dimethylacetal is then added and the mixture is heated at reflux for 20 min. After cooling and concentration in vacuo, the residue is taken up in dichloromethane and the organic phase washed with water, dried over Na ₂ SO 4 and concentrated in vacuo to a small volume. The crude product is precipitated by addition of ether. After filtration, 0.680 g (yield: 72.6%) of the title compound is obtained.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80.

NMR: ^{DMSO; H} δ (ppm): 3.0 (s, 3H); 3.15 (s. 3H); 3.30 (s, 3H);

4.90 (s, 2 H); 5.20 (s, 1H); 7.2-7.35 (m, 5H); 8.10 (s, 1H).

Step 2: N '- (1-Benzyl-5-iodo-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl) -N, N-dimethylformamidine

To a stirred solution of 0.68 g (2.38 mmol) of the compound obtained in step 1 above in 24 mL of anhydrous dichloromethane was added 0.64 g (2.85 mmol) of N-iodosuccinimide. After boiling for 30 min

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The reaction mixture was cooled and the organic phase was washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product is precipitated in ether to give 0.680 g (yield: 69.3%) of the title compound.

NMR: CDCl ₃ δ δ (ppm): 3.05 (s, 3H); 3.15 (s. 3H); 3.40 (s, 3H);

5.20 (s, 2H); 7.2-7.30 (m, 3H); 7.5-7.55 (m. 2H); 7.7 (s, 1H);

mp = 186.3 ° C.

Step 3: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester

To a stirred solution of 0.68 g (1.65 mmol) of the compound obtained in the previous step 2 in 45 ml of anhydrous DMF, 18 mg of Pd (OAC) ₂ , 8 mg of CuI, 330 mg of K ₂ CO ₃ and 0.22 ml are added successively ethyl acrylate. After boiling for 30 min, the reaction mixture was concentrated in vacuo. The residue is taken up in dichloromethane, the organic phase is filtered, washed twice with water, dried over Na ₂ SO ₄ and then concentrated in vacuo. The crude product is purified by chromatography on silica gel eluting with dichloromethane / methanol 97: 3 and then crystallized from ether to give 0.320 9 (yield: 57%) of the desired compound.

TLC: CH ₂ Cl ₂ / MeOH 97.5 / 2.5 Rf = 0.50.

NMR: CDCl 3 N δ (ppm): 1.40 (t, 3H); 3.70 (s, 3H); 4.40 (q. 2H);

5.30 (s, 2 H); 7.2-7.30 (m, 3H); 7.5-7.55 (m. 2H); 9.0 (s, 1H); 9.2 (s, 1 H).

Step 4: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido-2,3-d] pyrimidine-6-carboxylic acid

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193

Said compound is obtained by hydrolyzing the compound obtained in the previous step 3 in dioxane / water in the presence of LiOH.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.10.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 5.20 (s, 2H); 7.2-7.40 (m, 5H); 8.75 (s, 1H); 9.2 (s, 1H); 13.5 (bs, 1H).

HPLC = 100%.

Step 5: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide of

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 4 and piperonylamine.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.60.

NMR: DMSO * H δ (ppm): 3.60 (s, 3H); 4.40 (d, 2 H); 5.2 (s. 2H);

5.95 (s, 2 H); 6.75-6.95 (m, 3H); 7.2-7.40 (m, 5H); 8.85 (s, 1H);

9.2 (s, 1H); 9.25 (t, 1H).

IR: 3271, 1709, 1665, 1630, 1614, 1488, 1248, 1042,

937.797 cm ^-1 ;

mp = 174.9 ° C; HPLC: 97.5%.

Example 164

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid

Step 1: 1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid

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A solution of 1.3 g (4.17 mmol) of the compound obtained in Step 4 of Example 163 and 3.1 g (23 mmol) of AlCl ₃ in 44 ml of benzene was stirred at room temperature for 2 hours. Water / ice was added, the reaction mixture was extracted sequentially with ethyl acetate and dichloromethane, and the aqueous layer was acidified to pH 1 by addition of concentrated HCl. The resulting precipitate was collected by filtration and washed with 10 mL of methanol and 10 mL of dichloromethane to give the title compound (yield: 62.9%).

NMR: ^{DMSO; H} δ (ppm): 3.50 (s, 3H); 8.60 (s, 1H); 9.10 (s, 1H);

11.9 (bs, 1H); 13.5 (bs, 1H).

HPLC = 100%.

Step 2: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 2 and 4-methoxybenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.45.

NMR: DMSO ¹ H δ (ppm): 3.50 (s, 3H); 3.7 (s. 3H); 4.40 (d, 2 H); 6.85-6.95 (m, 2H); 7.25-7.30 (m, 2 H); 8.80 (s, 1H); 9.15 (s, 1H); 9.30 (t, IH); 11.85 (bs, 1H).

HPLC = 92%.

Step 3: methyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2 H -pyrido [2,3- d] pyrimidin-3-ylmethyl] benzoate

The title compound is obtained according to the procedure of step 2 of Example 34 using the compound obtained in the previous step 2 and methyl 4- (bromomethyl) benzoate. After precipitation in ether, 0.41 g (yield: 71.1%) of the title compound is obtained.

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TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.90.

NMR: δ DMSO ^X C (ppm): 3.60 (s, 3H); 3.80 (s, 3H); 3.90 (s, 3H);

4.45 (d, 2 H); 5.2 (s. 2H); 6.90 (dd, 2 H); 7.30 (dd, 2 H); 7.50 (dd, 2 H); 7.90 (dd, 9H); 8.90 (s, 1H); 9.20 (s, 1H); 9.30 (t, 1 H).

HPLC = 96.8%.

Step 4: 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid

The title compound is obtained by the procedure of Example 35 using the compound obtained in the previous step 3.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 4.45 (d, 2 H); 5.20 (s, 2H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.45 (d, 2 H); 7.90 (d, 2 H); 8.85 (s, 1 H); 9.20 (s, 1H); 9.30 (t, 1H); 12.90 (bs, 1H).

IR: 3292, 1718, 1695, 1667, 1633, 1609, 1497, 1301, 1242, 797 cm @ ^-1 ;

mp = 229.5 ° C; HPLC: 93.6%.

Example 165

3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained (0.11 g; 68.4% yield) by the procedure of Example 34 step 2 using the compound obtained in Example 164 step 2 and 4- (bromomethyl) benzonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

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NMR DMSO ⁴ Η δ (ppm

5.20 (s, 2H); 6.90

3.60 (s, 3K); 3.70 (s, 3H); 4.40 (d, 2 H);

(D 2 H); 7.30 (d, 2 H); 7.55 (d, 2 H); 7.80

9.20 (s, 1 H); 9.30 (t, 1 H).

IR: 3230, 2230, 1710, 1673, 1635, 1609, 1494, 1303,

1252, 794 cm ^-1 ;

mp = 197 ° C; HPLC: 97.2%.

Example 166

3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained following the procedure of Example 34 step 2 using the compound obtained in Example 164 step 2 and 4-fluorobenzyl bromide.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.70.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 4.40 (d, 2 H);

5.10 (s. 2H); 6.8-6.90 (m, 2 H); 7.1-7.2 (m. 2H); 7.25-7.35 (m, 2 H); 7.4-7.50 (m, 2 H); 8.85 (s, 1H); 9.15 (s, 1H); 9.30 (t, 1 H).

IR: 3260, 1709, 1664, 1616, 1497, 1245, 1221, 1035,

96 cm ^-1 ;

mp = 211.5 ° C; HPLC: 98.3%.

Example 167 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

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Step 1: 1-Benzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbaldehyde

A solution of 9.5 g (43.9 mmol) of 3-benzyl-6-methyl-1H-pyrimidine-2,4-dione (Synthetic Communications 1991, 2181-2188) and 129 ml of cold acetic acid is stirred for 5 min and then stirred 5.75 g of SeO 2 is added. The reaction mixture is heated to boiling for 2.5 h, then filtered and concentrated in vacuo. The residue is taken up in dichloromethane, the insoluble particles are separated and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel, eluting with dichloromethane / methanol 90: 5, to give 4.0 g of the desired compound (yield: 39.5%).

NMR: CDCl 3 ^X H δ (ppm): 5.20 (s, 2H); 6.30 (s, 1H); 7.2-7.30 (m, 3H); 7.40-7.50 (m, 2 H); 9.0 (bs, 1H); 9.60 (s, 1H).

Step 2: Dimethylhydrazone 1-benzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbaldehyde

To a stirred solution of 3.6 g (15.6 mmol) of the compound obtained in the previous step 1 in 80 mL of anhydrous DMF was added 1.2 mL (0.94 g, 15.6 mmol ·) of dimethylhydrazine. After stirring at room temperature for 1 h, the solvent was removed in vacuo and the residue was taken up in dichloromethane. The organic layer was washed, dried over Na ₂ SO ₄ and concentrated. The residue is purified by chromatography on silica gel, eluting with dichloromethane / methanol 97: 3, to give 2.5 g (yield: 59%) of the title compound.

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NMR: CDCl 3 ^2? (Ppm) 3.10 (s, 6H); 5.10 (s. 2H); 5.55 (s, 1H);

6.50 (s, 1H); 7.2-7.30 (m, 3H); 7.40-7.50 (m, 2 H); 8.50 (bs, 1H).

Step 3: 1-Benzyl-2,6-dioxo-3-methyl-1,2,3,6-tetrahydropyrimidine-4-carbaldehyde dimethylhydrazone

To a stirred solution of 2.3 g (8.45 mmol) of the compound obtained in Step 2 above in 58 mL of anhydrous DMF was added 2.3 mL (2.0 g, 1.69 mmol) of N, N'-dimethylformamide acetal. The reaction mixture was heated at 100 ° C for 10 min and then concentrated in vacuo. The residue is taken up in dichloromethane by addition of ether to give 1.75 g of the desired compound.

and the product precipitates (yield: 72.3%)

NMR: CDCl 3 ¹ H δ (ppm) 3.20 (s, 6H); 3.50 (s, 3H); 5.15 (s. 2H);

6.10 (s, 1 H); 6.60 (s, 1H); 7.2-7.30 (m, 3H); 7.40-7.50 (m, 2 H).

Step 4: methyl 1-benzyl-2,6-dioxo-3-methyl-1,2,3,6-tetrahydropyrimidine-4- (dimethylhydrazone carbaldehyde) -5-carboxylate

To a stirred solution of 1.7 g (5.94 mmol) of the compound obtained in the previous step 3 in 61 ml of anhydrous acetonitrile was added 1.68 g (7.1 mmol) of Pd (OAc) ₂ and 0.613 g (7.1 mmol) respectively. ) of methyl acrylate. After stirring at reflux for 20 min, the reaction mixture was separated by filtration and the filtrate was concentrated in vacuo. The residue is chromatographed on silica gel eluting with dichloromethane / methanol 97: 3 to give 1.40 g (63.6% yield) of the title compound.

NMR: CDCl 3 ‘H δ (ppm): 3.20 (s, 6H); 3.55 (s, 3H); 3.75 (s, 3H);

5.20 (s, 2H); 6.7C (s, 1H); 7.1-7.76 (m, 7H).

Step 5: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydrcoyrido [3,4-d] pyrimidine-6-carboxylic acid methyl ester

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A solution of 1.4 g (3.78 mmol) of the compound obtained in the previous step 4, 18 ml of chlorobenzene and 3.6 ml of acetic acid is stirred under boiling for 3 h, then concentrated in vacuo to give 1.4 g of a precipitate. The title compound (0.76 g; yield: 62%) was obtained by recrystallization of the crude product in 120 ml of ethyl acetate.

NMR: CDCl ₃ δ (ppm): 3.70 (s, 3H); 4.0 (s, 3 H); 5.30 (s, 2 H);

7.2-7.35 (m, 3H); 7.45-7.55 (m. 2H); 8.80 (s, 1H); 8.85 (s, 1H).

Step 6: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid

A mixture of 0.76 g (2.34 mmol) of the compound obtained in the previous step 5, 7.6 ml of methanol, 7.6 ml of water and 0.646 g (4.67 mmol) of K ₂ CO ₃ is stirred overnight at room temperature and then heat to boiling for 5 min. After cooling, water is added, the mixture is acidified to pH 1 and the resulting precipitate is dissolved in methanol / dichloromethane. The organic layer was washed with water, and concentrated in vacuo.

acquisition

The residue is precipitated in a mixture of 0.54 g (yield: 74%), dried with dichloromethane / ether to give the title compound.

NMR: DMSO ¹ H δ (ppm) 3.60 (s, 3H); 5.20 (s, 2H); 7.2-7.40 (m, 5H);

8.50 (s, 1H); 9.0 (s, 1H); 13.3 (bs, 1H);

mp = 240 ° C; HPLC = 100%.

Step 7: 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide of

The title compound was obtained according to the procedure of Example 1 using the compound obtained in the previous step 6 and piperonamidin.

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TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.60.

NMR: DMSO ¹ H δ (ppm): 3.65 (s, 3H); 4.40 (d, 2 H); 5.15 (s. 2H);

5.95 (s, 2 H); 6.75-6.85 (m, 2 H); 6.90 (s, 1H); 7.2-7.40 (m, 5H);

8.45 (s, 1H); 8.90 (s, 1H); 9.25 (t, 1H).

IR: 3387, 1716, 1662, 14875, 1442, 1250, 1239, 1040,

99 cm ^-1 ;

mp = 197.5 ° C; HPLC: 100%.

Example 168

Methyl 4- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-l, 4-dihydro-2H-pyrido [3,4-d] pyrimidine-3-ylmethyl] benzoate

Step 1: 1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid

The compound obtained in Step 6 of Example 167 (3.3 g; 10.6 mmol) was treated as described in Step 164 of Example 164 to give 2.0 g (yield: 85.3%) of the title compound.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 8.40 (s, 1H); 8.95 (s, 1H);

12.0 (s, 1 H); 12.90 (bs, 1H).

HPLC = 100%.

Step 2: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained (yield: 78%) according to the procedure of Example 1 using the compound obtained in the previous step 1 and 4-methoxybenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.50.

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NMR: DMSO δ (ppm): 3.60 (s, 3H); 3.75 (s, 3H); 4.40 (d, 2 H);

6.85 (dd, 2 H); 7.25 (dd, 2 H); 8.40 (s, 1H); 8.85 (s, 1H); 9.20 (t, IH); 12.0 (s, 1 H).

HPLC = 99%.

Step 3: methyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoate

The title compound was obtained (0.2 g; yield 77%) by the procedure of Step 2 of Example 34 using the compound obtained in the previous Step 2 and methyl 4- (bromomethyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.80.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.70 (s, 3H); 3.85 (s, 3H);

4.50 (d, 2 H); 5.20 (s, 2H); 6.85 (d, 2 H); 7.20 (d, 2 H); 7.50 (d, 2 H); 7.90 (d, 2 H); 8.5 (s, 1H); 8.90 (s, 1H); 9.20 (t, 1H).

IR: 3396, 1719, 1661, 1439, 1279, 1250, 1110, 753 cm @ ^-1 ;

mp 211.1 ° C; HPLC: 99.5%.

Example 169 t-Butyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoate

The title compound was obtained (yield: 80.4%) by the procedure of Example 34 step 2 using the compound obtained in Example 168 step 2 and t-butyl 4-bromomethylbenzoate.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.80.

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NMR: DMSO? (Ppm): 1.50 (s, 9H); 3.65 (s, 3H); 3.75 (s, 3H);

4.40 (d, 2 H); 5.20 (s, 2H); 6.85 (dd, 2 H); 7.25 (dd, 2 H); 7.45 (dd, 2 H); 7.85 (dd, 2 H); 8.50 (s, 1H); 8.90 (s, 1H); 9.2 (t, 1H).

HPLC = 98%.

Example 170

- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 3-methoxybenzylamide

The title compound was obtained (yield: 62.4%) following the procedure of Example 1 using the compound obtained in Step 1 of Example 168 and 3-methoxybenzylamine.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.50.

NMR: DMSO ^: δ (ppm): 3.60 (s, 3H); 3.75 (s, 3H); 4.50 (d, 2 H); 6.75-6.95 (m, 3H); 7.20-7.30 (m, IH); 8.40 (s, 1H); 8.85 (s, 1H); 9.25 (t, 1 H); 12.0 (s, 1 H).

HPLC = 98%.

Step 2: t-butyl 4- [6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethylbenzoate

The title compound was obtained (yield: 80.4%) by the procedure of Step 2 of Example 34 using the compound obtained in the previous Step 1 and t-butyl 4- (bromomethyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.80.

NMR: DMSO 1 H δ (ppm): 1.50 (s, 9H); 3.65 (s, 3H); 3.75 (s, 3H);

4.50 (d, 2 H); 5.20 (s, 22); 6.80-6.95 (m, 3H); 7.20-7.30 (m, 1H);

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7.5 (dd, 2 H); 7.85 (dd, 2 H); 8.50 (s, 1H); 8.95 (s, 1H); 9.3 (t, 1 H).

HPLC = 93.6%.

Step 3: 4- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid

The title compound was obtained following the procedure of Example 169, step 2, using the compound obtained in the previous step 2.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.60.

NMR: DMSO ^{Τ Η δ} (ppm): 3.65 (s, 3H); 3.75 (s, 3H); 4.50 (d, 2 H);

5.20 (s, 2H); 6.75-6.80 (s, 1H); 6.90 (s, 2 H); 7.20-7.25 (m, 1 H);

7.45 (d, 2 H); 7.85 (d, 2 H); 8.5 (s, 1H); 8.90 (s, 1H); 9.30 (t, IH); 12.95 (bs, 1H).

IR: 3378, 1712, 1660, 1600, 1439, 1266, 1056, 790 cm @ ^-1 ;

mp = 208.1 ° C; HPLC: 96.6%.

Example 171

3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Example 34, Step 2, using the compound obtained in Example 168, Step 2, and (4-bromomethyl) benzonitrile.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.80.

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NMR: DMSO ^{λ Η δ} (ppm): 3.65 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H);

5.25 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.55 (d, 2 H); 7.80 (d, 2 H); 8.5 (s, 1H); 8.95 (s, 1H); 9.20 (t, 1H).

IR: 3391, 2298, 1716, 1662, 1443, 1331, 1251, 789 cm @ ^-1 ;

mp = 230 ° C; HPLC: 98.8%.

Example 172

3-Benzyl-l-methyl-6- (3-phenyl-propionyl) -lH-quinazoline-2,4-dione

The compound of Preparation C is reacted with SOCl ₂ in TF to give its chloride, which reacts with phenethylmagnesium bromide and CuI in the presence of TF. After the usual work-up, the title compound is obtained.

NMR: CDCl ₃ δ (ppm): 3.0 (m, 2H); 3.30 (m, 2 H); 3.60 (s, 3H);

5.25 (s, 2 H); 7.10-7.35 (m, 9H); 7.56 (m, 2 H); 8.3 (m, 1H); 8.80 (s, 1 H);

mp = 155 ° C; HPLC: 98.0%.

Example 173 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (E) -3-pyridin-4-ylalyl ester

NMR CDCl ₃ δ (ppm) 3.60 (s, 3H); 5.0 (d, 2 H); 5.30 (s, 2 H); 6.56.7 (m, 2 H); 7.15-7.35 (m, 6H); 7.55 (m. 2H); 8.40 (m, 1H); 8.60 (m, 2 H); 9.0 (s, 1 H).

mp 147 ° C; HPLC 97.5%.

Example 174

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NMR CDCl ₃ δH δ (ppm): 3.60 (S, 3H); 5.0 (D 2 H); 5.30 (s, 2 H); 6.5 (m, 1 H); 6.8 (d, 1H); 7.30 (m, 5H); 7.60 (M, 2H); 7.7 (d, 1H); 8.40 (D, 1H); 8.55 (m, IH); 8.70 (S, lH); 9.0 (S, lH). temperature mp = 184 ° C; HPLC: 99.6% • Example 175

3-Benzyl-1-methyl-6- [2- (pyridin-4-ylsulfanyl) acetyl] -1H-quinazoline-2,4-dione

TLC: CH ₂ Cl ₂ / MeOH 98: 2 Rf = 0.20.

NMR: CDCl ₃ δ (ppm): 3.65 (s, 3H); 4.45 (s, 2 H); 5.25 (s, 2 H);

7.18 (d, 2 H); 7.20-7.35 (m, 4H); 7.50 (d, 2 H); 8.3 (d, 1H); 8.40 (d, 2 H); 8.80 (s, 1 H).

IR: 1706, 1693, 1657, 1610, 1574, 1508, 1480, 1448, 1428, 1321, 1307, 1206, 1093, 831, 810, 782, 703 cm ^{@ -1} ;

mp = 187 ° C; HPLC: 98.0%.

Example 176

3- (4-Aminomethylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid methoxybenzylamide

The title compound is obtained by catalytic hydrogenation of the compound of Example 60 using Raney-Ni and NH ₃ in methanol.

TLC: CH ₂ Cl ₂ / MeOH / NH ₄ OH 90: 10: 1 Rf 0.25.

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NMR: CDCl ₃ δ (ppm): 1.45-1.70 (m, 2H); 3.6 (s. 3H); 3.8 (m, 5 H); 4.55 (d, 2 H); 5.22 (s, 2 H); 6.74 (m, IH); 6.86 (d, 2 H);

7.2-7.30 (m, 5H); 7.44 (d, 2 H); 8.28 (d, IH); 8.48 (s, 1K).

IR: 3370, 1702, 1655, 1640, 1617, 1542, 1508, 1477,

1324, 1303, 1247, 1173, 1032, 829, 786, 756 cm ^-1 ;

mp = 187 ° C; HPLC: 98.4%.

Example 177

3- (2'-Cyanobiphenyl-4-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure for Step 2 of Example 34 using 2- (4-bromomethyl-phenyl) -benzonitrile.

TLC: CH ₂ Cl ₂ / MeOH 98.5: 1.5, Rf = 0.20.

NMR: CDCl 3 ¹ H δ (ppm): 3.65 (s, 3H); 3.80 (s, 3H); 4.55 (d, 2 H);

5.30 (s, 2 H); 6.55-6.65 (m, IH); 6.25 (d, 2 H); 7.2-7.30 (m, 3H);

7.35-7.50 (m, 4H); 7.55-7.65 (m, 3H); 7.75 (d, 1H); 8.25-8.35 (m, IH); 8.45 (s, 1 H).

IR: 1702, 1661, 1629, 1508, 1478, 1332, 1242, 1036,

33.766 cm ^-1 ;

mp = 200 ° C; HPLC: 99.8%.

Example 178

1-Methyl-2,4-dioxo-3- [2 (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound was obtained according to the procedure of Step 2 of Example 34 using 5 - [(4-bromomethyl) biphenyl] tecrazole.

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TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50.

NMR: DMSO ^{Ο Η δ} (ppm): 3.55 (s, 3H); 3.75 (s, 3H); 4.40 (d, 2H);

5.15 (s. 2H); 6.90 (d, 2 H); 7.05 (d, 2 H); 7.25 (d, 4H); 7.45-7.70 (m, 6H); 8.30 (d, 1H); 8.6 (s, 1H); 9.25 (m, IH).

IR: 2943, 1702, 1656, 1618, 1510, 1477, 1450, 1323,

1302, 1247, 1032, 829, 814, 782, 757 cm &lt; ^{-1 &gt};;

HPLC: 99.6%.

Example 179

Methyl 4 '- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] -biphenyl-2-carboxylate

The title compound was obtained according to the procedure of Example 34 step 2 using methyl 4- (bromomethylphenyl) benzoate.

TLC: CH ₂ Cl ₂ / MeOH 97: 3, Rf = 0.30.

NMR: ^{DMSO; H} δ (ppm): 3.61 (s, 3H); 3.62 (s, 3H); 3.80 (s, 3H);

4.55 (d, 2 H); 5.30 (s, 2 H); 6.65 (t, 1H); 6.85 (d, 214); 7.2-7.30 (m, 6H); 7.35-7.40 (m, 1H); 7.45-7.55 (m. 3H); 7.80 (d, IH); 8.27 (d, 1H); 8.47 (s, 1 H).

IR: 1707, 1668, 1656, 1638, 1616, 1509, 1478, 1330,

1294, 1248, 1089, 765, 754 cm ^-1 ;

mp = 172 ° C; HPLC: 99.7%.

Example 180

4 '- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] biphenyl-2-carboxylic acid

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The title compound was obtained according to the procedure for Step 2-4 of Preparation B using the compound of Example 179.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.40.

NMR: DMSO ^{Χ Η δ} (ppm): 3.57 (s, 3H); 3.72 (s, 3H); 4.42 (d, 2 H);

5.20 (s, 2H); 6.90 (d, 2 H); 7.2 5-7.4 δ (m, 8H); 7.50-7.60 (m, 2 H);

7.70 (d, IH); 8.26 (d, IH); 8.60 (s, 1H); 9.17-9.27 (m, IH); 12.513.2 (m, IH).

IR: 1698, 1668, 1655, 1639, 1612, 1508, 1479, 1330,

1304, 1248, 765, 754 cm ^-1 ;

mp = 175 ° C; HPLC: 100%.

Example 181

Ethyl 2-fluoro-4- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate

The title compound was obtained according to the procedure of Step 34 of Example 34 using methyl 4- (bromomethyl) -2-fluorobenzoate.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

NMR: CDCl ₃ δ (ppm): 1.30 (t, 3H); 3.60 (s, 3H); 3.80 (s, 3H);

4.35 (q, 2 H); 4.60 (m, 2 H); 5.30 (s, 2 H); 6.55 (m, IH); 6.90 (m, 2 H); 7.30 (m, 5H); 7.90 (m, IH); 8.30 (m, IH); 8.50 (s, 1H);

mp = 156 ° C; HPLC: 100%.

Example 182

2-Fluoro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid

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The title compound was obtained according to the procedure for Step 2-4 of Preparation B using the compound of Example 181.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.20.

NMR: ^{DMSO; H} δ (ppm): 3.60 (s, 3H); 3.75 (s, 3H); 4.40 (m, 2 H); 5.20 (s, 2H); 6.90 (m, 2 H); 7.30 (m, 4H); 7.60 (d, IH); 7.80 (m, 1H); 8.30 (m, 1H); 8.70 (s, 1H); 9.2 (s, 1H); 13.2 (s, 1H);

mp = 160 ° C; HPLC: 100%.

Example 183

2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-dimethylaminoethyl ester

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.20.

NMR: CDCl ₃ δ (ppm) 2.3 (s, 6H); 2.60 (m, 2 H); 3.60 (s, 3H);

3.75 (s, 3H); 3.85 (s, 3H); 4.35 (m, 2 H); 4.55 (m, 2 H); 5.25 (s, 2 H); 6.50 (m, IH); 6.80 (m, 2 H); 7.10 (d, 1H); 7.25 (m, 4H); 7.70 (d, 1H); 8.25 (m, IH); 8.5 (s, 1H);

mp = 130 ° C; HPLC: 97.3%.

Example 184

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -2-methylbenzoic acid 2-dimethylaminoethyl ester

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.60.

NMR: CDCl 3 ^X H δ (ppm) 2.3 (s, 6H); 2.55 (s, 3H); 2.70 (m, 2 H); 3.60 (s, 3H); 3.80 (s, 3H); 4.40 (m, 2 H); 4.60 (m, 2 H); 5.20

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8.30 (m, IH); 8.5 (s, 1H);

mp = 146 ° C; HPLC: 99%.

Example 185

1-Methyl-2,4-dioxo-3- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) benzyl] -4-methoxybenzylamide -1,2,3, 4-tetrahydroquinazoline-6-carboxylic acid

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.30.

NMR: DMSO ^{Σ Η δ} (ppm) 3.2 (m, 1H);

4.40 (d, 2H); 5.20 (s, 2H); 6.90 (m, 2 H); 7.55 (m, IH); 7.70 (m, 2H)

3.55 (s, 3H); 3.70 (s, 3H);

(M, 2H); 7.25 (m, 2 H); 7.40

8.30 (m, 1H); 8.60 (s, 1H);

9.2 (m, IH);

mp = 305 ° C; HPLC: 100%.

Example 186 {4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylphenyl} acetic acid

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.35.

NMR: DMSO ¹ H δ (ppm) 3.50 (m, 5H); 3.70 (s, 3H); 4.40 (d, 2 H); 6.80 (d, 2 H); 7.20 (m, 4H); 7.40 (d, 2 H); 7.60 (d, IH); 8.30 (d, IH); 8.60 (s, 1 H); 9.2 (t, 1 H).

IR = 1717, 1645, 1619, 1501, 1298, 1240, 823, 750 cm ^-1 ;

HPLC: 100%.

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Example 187 1-Methyl-3- (1-naphthalen-1-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl) amide

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.58.

NMR: ^{DMSO; H} δ (ppm) 2.0 (d, 3H); 3.45 (s, 3H); 4.40 (d, 2 H); Δ 0.00 (s, 2H); 6.80-6.95 (m, 4H); 7.4-7.50 (m, 3H); 7.55 (t, 1 H); 7.85-8.0 (m, 4H); 8.20 (d, 1H); 8.6 (s, 1H); 9.15 (t, 1H).

IR: 1656, 1618, 1503, 1440, 1254, 1040, 777, 754 cm @ ^-1 ;

mp = 157 ° C; HPLC: 96.2%.

Example 188

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid

To a stirred solution of 0.5 g (0.9 mmol) of the compound obtained in Example 169 in 50 mL of dichloromethane was added 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature overnight and then 60 mL of ether was added. The product crystallizes to give 0.44 g (yield: 100%) of the title compound after filtration.

TLC: CH ₂ Cl ₂ / MeOH 90: 5 Rf = 0.60.

NMR: ^{DMSO; H} δ (ppm): 3.65 (s, 3H); 3.75 (s, 3H); 4.45 (d, 2 H); 5.25 (s, 2 H); 6.90 (d, 2 H); 7.25 (d, 2 H); 7.50 (d, 2 H); 7.90 (d, 2 H); 8.5 (s, 1H); 8.95 (s, 1H); 9.20 (1H), 12.85 (bs, 1H).

IR: 3388, 1715, 1662, 1475, 1442, 1247, 791 cm &^lt; -1 &gt;;

mp = 264.4 ° C; HPLC: 98.9%.

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Example 189 3- (3-Fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

To a mixture of 0.5 g (1.5 mmol) of the compound of Preparation D and dimethylformamide (10 mL) was added 0.38 g of EDAC.HCl (1.9 mmol), 0.27 g of HOBT (1.9 mmol), and then 0.21 g of 4-pyridylbenzylamine (1.9 mmol). After stirring at room temperature for 48 hours, water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (4 x 20 mL) and then dried over MgSO ₄ . Crystallization from hot ethyl acetate gave 0.13 g (yield: 20%) of the title compound.

Mass spectrum: m / z (APCI, AP +) 419.2 [M] &lt; ^{+ &gt};.

CHN analysis: calcd C 66.02; H, 4.58; N, 13.39; found C 65.73; H, 4.47; N, 13.36.

Example 190 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) amide

The title compound (0.10 g; yield: 17%) was obtained according to the procedure of Example 189 but using 2-methoxy-4-pyridyl-benzylamine.

Mass Spectrum: m / z (APCI, AP +) 449.2 [M] ⁺

CHN analysis: C ₂ 4 H ₂₁ FN ₄ O ₄ .0, 1 H ₂ O Calcd (%): 12.44 CN; Found (%): C 63.66; H, 5.07; N, 12.16.

64.02; H, 4.75;

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Example 191 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

The title compound (0.11 g; yield 26%) was obtained according to the procedure of Example 189 but using 3-pyridylbenzylamine.

Mass spectrum: m / z (APCI, AP +) 419.1 [M] &lt; ^{+ &gt};.

CHN analysis: C 23 H 19 FN ₄ O ₃ . 1, 9 H ₂ O Calcd (%): C, 62.78; H, 4.90; N, 12.73; Found (%): C, 62.75; H, 4.90; N, 12.73.

Example 192

3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound (0.12 g; yield: 35%) was obtained according to the procedure of Example 189 but using 4-methoxybenzylamine.

Mass spectrum: m / z (APCI, AP +) 448.1 [M] ⁺ .

CHN analysis: C ₂₅ H ₂₂ FN ₃ O ₄ .0.1H ₂ O calculated (%) C 66.84; H, 4.98; N, 9.35; Found (%): C, 66.57; H, 4.83; N, 9.03.

Example 193

3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

The title compound (0.20 g; yield: 59%) was obtained according to the procedure of Example 189 but using 3-methoxybenzylamine.

Mass spectrum: m / z (APCI AP +) 448.1 [M] ⁺ .

CHN analysis: C 5 H ₂₂ FN ₂ O _{3 4} Calcd (%) C, 67.11; H, 4.96; N, 9.39;

Found (%): C, 66.82; H, 4.87; N, 9.11.

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Example. 194 1-Ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound (0.13 g; yield: 20%) was obtained according to the procedure of Example 189 but using the compound of Preparation E and 4-pyridylbenzylamine.

Mass spectrum: m / z (APCI, AP +) 433.2 [M] ⁺ .

CHN analysis: calculated (%): C, 66.66; H, 4.89; N, 12.96; found (%): C, 66.26; H, 4.71; N, 19.78.

Example 195 1-Ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

The title compound (0.18 g; yield: 51%) was obtained according to the procedure for EXAMPLE 189 but using the compound of Preparation E and 3-pyridyl-benzylamine.

Mass spectrum: m / z (APCI, AP +) 433.1 [M] ⁺ .

CHN analysis: calculated (%): C 66.66; H, 4.89; N, 12.96; Found (%): C, 66.43; H, 5.03; N, 12.84.

Example 196

3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

Step 1: methyl 3- (4-bromobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

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The title compound (4.6 g; yield: 59%) was obtained according to the procedure of Step 1 of Preparation D but using 4-bromobenzyl isocyanate.

Mass spectrum: m / z (APCI, AP +) 388.9 [M] &lt; ^{+ &gt};.

CHN analysis: calculated (%): C, 52.46; H, 3.37; N, 7.20; Found (%): C, 52.16; H, 3.30; N, 7.30.

Step 2: methyl 1-methyl-3- (4-bromobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound (1.49 g; yield: 71%) was obtained according to the procedure of Step 2 of Preparation D but using the compound obtained in the previous Step 1.

Mass spectrum: m / z (APCI AP +) 404.9 [M] &lt; ^{+ &gt};.

CHN analysis: calcd C 53.62; H, 3.75; N, 6.95; found C 53.24; H, 3.71; N, 6.84.

Step 3: 1-Methyl-3- (4-bromobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound (1.3 g; yield: 87%) was obtained according to the procedure of step 2-4 of preparation D but using the compound obtained in previous step 2.

Mass spectrum: m / z (APCI AP +) 388.9.

CHN analysis: calculated (%): C, 52.46; H, 3.37; N, 7.20; Found (%): C, 52.12; H, 3.30; N, 7.11.

Step 4: 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

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The title compound (0.24 g; yield: 76%) was obtained according to the procedure of Example 189 but using the compound obtained in the previous step 3 and 4-methoxybenzylamine.

Mass spectrum: m / z (APCI, AP +) 508 [M] &lt; ^{+ &gt};.

CHN analysis: C 5 H _{22 2 4} BrN3O .0,2H ₂ 0: Calcd (%): C 58.65; H, 4.41; N, 8.21; Found (%): C 58.32; H, 4.32; N, 8.12.

Example 197 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) amide

The title compound (0.22 g; yield: 33%) was obtained according to the procedure of Example 189 but using the compound obtained in the previous step 3 and 2-methoxy-4-pyridyl-benzylamine.

NMR: DMSO δ (ppm): 3.52 (3H, s); 3.79 (3 H, s); 4.43 (2 H, d);

5.09 (2 H, S); 6.66 (1H, s); 6.89 (1H, d); 7.26-7.56 (5H, m); 8.06 (1H, d); 8.24-8.26 (1H, m); 8.61 (lH, m); 9.31 (1H, t);

mass spectrum: m / z (APCI, AP +) 509 [M] &lt; + &gt;.

Example 198 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

Step 1: methyl 3- (3,4-difluoro-benzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound is obtained in 51% yield according to the procedure of steps 1-5 to 2-5 of Preparation B using the compound of Preparation A and 3,4-difluorobenzylamine.

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NMR: DMSO ¹ H δ (ppm): 3.86 (3H, s); 5.05 (2H, s), 6.66 (1H, s);

7.18-7.43 (4 H, m); 8.18 (1H, dd); 8.47 (1H, s);

mass spectrum: m / z (APCI AP +) 347.1 [M] ⁺ .

Step 2: methyl 1-methyl-3- (3,4-difluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound (1.5 g; yield: 72%) was obtained by the procedure of Step 2 of Preparation D but using the compound obtained in the previous Step 1.

Mass spectrum: m / z (APCI AP +) 361.0 [M] ⁺ .

CHN analysis: calculated (%): C 60.00; H, 3.92; N, 7.77; Found (%): C, 60.05; H, 3.85; N, 7.72.

Step 3: 1-Methyl-3- (3,4-difluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound (1.1 g; yield: 82%) was obtained according to the procedure of step 2-4 of preparation B but using the compound obtained in previous step 2.

Mass spectrum: m / z (APCI, AP +) 437.0 [M] ⁺ .

CHN analysis: calculated (%): C 58.96; H, 3.49; N, 8.09; Found (%): C, 58.67; H, 3.99; N, 7.27.

Step 4: 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

The title compound (0.48 g; yield: 79%) was obtained according to the procedure of Example 189 but using the compound obtained in the previous step 3 and 3-pyridylbenzylamine.

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Mass spectrum: m / z (APCI, AP +) 437.1 [th].

CHN analysis: C ₃ H ₁₈ F ₂ N ₄ O ₃ . 0.2 H ₂ O Calcd (%): C, 62.78; H, 4.21; N, 12.73; Found (%): C, 62.50; H, 4.13; N, 12.82.

Example 199 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound (0.23 g; yield: 38%) was obtained according to the procedure of Example 189 but using the compound obtained in Step 3 of Example 198 and 4-pyridylbenzylamine.

Mass spectrum: m / z (APCI, AP +) 437.1 [M] ⁺ .

CHN analysis: C ₂₃ H ₁₈ F ₂ N ₄ O ₃ Calcd (%): C 63.30; H, 4.16; N, 12.84; Found (%): C 63.19; H, 4.07; N, 12.81.

Example 200

3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound (0.11 g; yield: 39%) was obtained according to the procedure of Example 189 but using the compound obtained in Step 3 of Example 198 and 4-methoxybenzylamine.

Mass spectrum: m / z (APCI AP +) 466.2 [M] &lt; ^{+ &gt};.

CHN analysis: C ₂₅ H ₂₁ F ₂ N ₃ O ₄ calculated (%) C 64.51; H, 4.55; N, 9.03; Found (%): C, 64.41; H, 4.53; N, 8.87.

Example 201 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

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Step 1: methyl 3- (3-chloro-4-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound was obtained in 18.1% yield by the procedure of Step 1-5 to Step 2-5 of Preparation B using the compound of Preparation A and 3-chloro-4-fluorobenzylamine.

Mass Spectrum: m / z (APCI, AP ⁺ ) 361.0 [M] ⁺ .

Step 2: methyl 1-methyl-3- (3-chloro-4-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate

The title compound (0.5 g; yield: 72%) was obtained according to the procedure of Step 2 of Preparation D but using the compound obtained in the previous Step 1.

Mass spectrum: m / z (APCI, AP +) 377.0 [M] &lt; ^{+ &gt};.

CHN analysis: calculated (%): C, 57.38; H, 3.75; N, 7.44; Found (%): C, 57.34; H, 3.73; N, 7.27.

Step 3: 1-Methyl-3- (3-chloro-4-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid

The title compound (0.45 g; yield: 92%) was obtained according to the procedure of step 2-4 of preparation B but using the compound obtained in previous step 2.

Mass Spectrum m / z (APCI, AP +) 363.0 [M] ⁺ .

CHN analysis: calculated (%): C, 56.29; H, 3.33; N, 7.72; found C 56.24; H, 3.21; N, 7.64.

Step 4: 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

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The title compound (0.17 g; yield: 69%) was obtained according to the procedure of Example 189 but using the compound obtained in the previous step 3 and 4-pyridylbenzylamine.

Mass spectrum: m / z (APCI, AP +) 453.1 [M] &lt; ^{+ &gt};.

CHN analysis: C ₂₃ H ₁₈ F ₂ N ₄ O ₃ .1 1 H ₂ O Calcd (%): C, 58.4 4; H, 4.31; N, 11.85; Found (%): C 58.23; H, 4.23; N, 11.75.

Example 202

3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide

The title compound (0.21 g; yield: 80%) was obtained according to the procedure of Example 189 but using the compound obtained in Step 3 of Example 201 and 4-methoxybenzylamine.

Mass spectrum: m / z (APCI AP +) 482.1.

CHN analysis: C ₂₅ H ₂₁ ClFN ₃ O ₄ calculated (%): C 62.31; H, 4.39; N, 8.72; Found (%): C, 62.12; H, 4.37; N, 8.51.

Example 203

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethylbenzoate (2-hydroxyethyl) trimethylammonium

To a suspension of 0.5 g (1.05 mmol) of the compound of Example 34 in hot methanol was added 0.22 g (1.03 mmol) of choline bicarbonate. The mixture was heated to boiling for 1 h, then cooled and concentrated. The resulting solid is recrystallized from ethanol to give 0.41 g (yield: 68%) of the title compound.

CHN analysis: C 31 H 36 N 4 O 3 - 0.5H ₂ Calcd (%): C 63, 58; H, 6.37; N, 9.57; Found (%): C 63.32; H, 6.58; N, 9.57.

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Example 204

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid semisolid

To a suspension of 0.5 g (1.05 mmol) of the compound of Example 34 in warm tetrahydrofuran was added 1.05 mL of 1M NaOH solution. The mixture was stirred for 0.5 h, then added in one portion 0.058 g (0.525 mmol) of CaCl _second The mixture was stirred for 2 hours and then concentrated, ethanol was added and the mixture was filtered. The residue was dried at 88 ° C in a vacuum oven for 72 hours to give 0.49 g (yield: 94%) of the title compound.

CHN analysis: C ₅ H _{4 4} CaN ₆ O ₁₂ · 1.0H ₂ O Calcd C (%): 62.27; H, 4.62;

N, 8.38; Found (%): C 61.95; H, 4.70; N, 8.34.

Example 205

4- (6- (4-Methoxybenzyl · carbamoyl)) - 1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid, magnesium salt

To a suspension of 0.5 g (1.05 mmol) of the compound of Example 34 in warm tetrahydrofuran was added 1.05 mL of 1M NaOH solution. The mixture was stirred for 0.5 h and then MgCl ₂ (0.052 g, 0.525 mmol) was added in one portion. The mixture was stirred for 2 hours and then concentrated, ethanol was added and the mixture was filtered. The residue was dried at 88 ° C in a vacuum oven for 72 hours to give 0.49 g (yield: 96%) of the title compound.

CHN analysis: C ₅ H ₄₄ MgN ₆ O ₁₂ . 1, 0H ₂ O Calcd (%): C, 63.26; H, 4.70; N, 8.51; Found (%): C 63.07; H, 4.89; N, 8.50.

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Example. 3- (4-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridazin-4-ylmethyl) amide

To a suspension of the compound of Step 1 of Example 33 (1.00 g;

4.54 mmol), EDAC (1.13 g, 5.90 mmol) and HOBT (0.675 g, 5.00 mmol) in 20 mL of DMF were added a solution of 4-aminomethylpyridine (0.507 mL, 5.00 mmol). The light orange suspension was stirred overnight at room temperature. After 24 h, the reaction mixture was concentrated to give an off-white solid, which was successively washed with 10 mL of ethyl acetate, saturated Na ₂ CO ₃ solution and 10 mL of H ₂ O to give 1.20 g (yield: 85.7%) of the product.

M.p .: 141-145 ° C;

mass spectrum (APCI +): m / z 309.1.

Step 2: 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

To a suspension of the compound obtained in Step 1 above (0.200 g, 0.645 mmol) in 6 mL of DMF was added Cs ₂ CO ₃ (0.630 g, 1.93 mmol). The mixture was stirred at room temperature for 30 min and then a solution of 4-chlorobenzyl bromide (0.132 g, 0.645 mmol) in 2 mL DMF was added dropwise and the mixture was stirred overnight. The resulting white solid (cesium salt) was filtered and the solution was concentrated, the resulting suspension was diluted with 10 mL of ethyl acetate and filtered again. The filtrate was concentrated and the residue was overlayed with 10 mL of ethyl acetate to give 0.26 g (yield: 92.9%) of a white solid corresponding to the desired compound.

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Melting point: 228-230 ° C.

CHN analysis: Ο2 ₃ Η ₁₉ Ν4Ο ₃ Ο1 calculated (%): C 63.52; H, 4.40; N, 12.88; Found (%): C, 63.40; H, 4.41; N, 12.84.

Example 207 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide

The title compound (0.2 g yield: 74.1%) was obtained following the procedure of Example 206 of Steps 1 to 2 but using (in Step 2) 4-fluorobenzyl bromide.

Mp 210-212 ° C.

CHN analysis: C 23 H 19 N 4 O 3 F calculated (%): C 66.02; H, 4.58; N, 13.39; Found (%): C 65.74; H, 4.60; N, 13.03.

Example 208 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) -amide

The title compound (1.18 g; yield: 83.7%) was obtained following the procedure from Example 206, step 1, but using 3-aminomethylpyridine.

Mass spectrum (APCI +): m / z 309.1 (MH +).

NMR (400 MHz), DMSO-d ₅ δ 3.43 (s, 3H, NCH ₃ ), 4.47 (d, J = 5.86)

Hz, 2H, NCH ₂ Ar), 7.31-7.34 (m, 1H, Ar H), 7.48 (d, J = 8.79 Hz, 1H, Ar H), 7.70 (d, J = 7.82 Hz, 1H, ArH), 8.20 (dd, J = 8.79, 1.95 Hz,

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1H, ArH), 8.42-8.43 (m, 1H, ArH), 8.53 (d, J = 2.20 Hz, 2H,

ArH), 9.30 (t, J = 5.62, 1H, ArH), 11.65 (s, 1H, NH).

Step 2: 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide

The title compound (0.25 g; yield: 82.6%) was obtained according to the procedure of Example 206, step 2, but using the compound obtained in the previous step 1 and 4-fluorobenzyl bromide.

Melting point: 166-168 ° C.

CHN analysis calcd for C ₂₃ H ₉ N ₄ O ₃ F: (%) C 65, 79; H, 4.60; N, 13.34; Found (%): C, 65.40; H, 4.40; N, 13.18.

Example 209 3- (4-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) -amide

The title compound (0.25 g; yield 89.3%) was obtained according to the procedure of Example 206 of Step 2 but using the compound obtained in Step 1 of Example 208 and 4-chlorobenzyl bromide.

Melting point: 173-175 ° C.

CHN analyzes (%) calculated for C ₂₃ H ₉ N ₄ O ₃ Cl: C 62.77; H, 4.48; N, 12.73; found: C 62.39; H, 4.46; N, 12.71.

Example 210

3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

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The title compound (1.29 g; yield 83.8%) was obtained according to the procedure of Example 206 of Step 1 but using 3-methoxybenzylamine.

Melting point: 235-238 ° C.

Step 2: 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

The title compound (0.25 g; yield 95%) was obtained by the procedure of Example 206, step 2, but using the compound obtained in the previous step 1 and 4-fluorobenzyl bromide.

Melting point: 176-178 ° C.

CHN analysis (%) calculated for C 25 H 22 N 3 O 4 F: C 67.11; H, 4.96; N, 9.39; Found: C, 66.99; H, 4.99; N, 9.18.

Example 211

3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide

The title compound (0.25 g; yield: 92%) was obtained according to the procedure of Example 206 of Step 2 but using the compound obtained in Step 1 of Example 210 and 4-chlorobenzyl bromide.

Melting point: 178-180 ° C.

CHN analysis (%) calculated for C 25 H 22 N 3 O 4 Cl: C 64.60; H, 4.79; N, 9.04; found: C 64.22; H, 4.72; N, 8.84.

Example 212 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) amide

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Step 1: 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide

The title compound (1.00 g; yield 76.9%) was obtained according to the procedure of Example 206 of Step 1 but using (2-methoxy-pyridin-4-yl) -methylamine.

Mp 215-218 ° C;

mass spectrum (APCI +): m / z 339.1 (MH +).

Step 2: 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide

The title compound (0.07 g; yield 26.5%) was obtained according to the procedure of Example 206, step 2, but using the compound obtained in the previous step 1 and 4-fluorobenzyl bromide.

Melting point: 174-175 ° C.

CHN analysis (%) calculated for C24H21N4O4F: C 64.20; H, 4.73; N, 12.48; found: C 63.88; H, 4.73; N, 12.08.

Example 213 3- (4-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) -amide

desired compound (0.09 g; yield 33%) is obtained following the procedure of Example 206, step 2, but in use compound obtained in step 1 of the example 212 and 4-chlorobenzyl bromide Melting point: Mp 169-170 ° C • CHN analysis (%) calculated for C 24 H 21 N 4 O 4 Cl: C 62.02; H, 4.61; N, 11.98; found Found: C, 62.01; H, 5.01; N, 11.70.

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Example 214 t-Butyl 1- {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} cyclopropanecarboxylate

The title compound (0.5 g; yield 67%) was obtained according to the procedure of Example 206, steps 1 to 2, but when used in the step

4-methoxybenzylamine and in step 2 t-butyl 1- (4-bromomethylphenyl) cyclopropanecarboxylate.

M.p .: 148-149 ° C.

CHN analysis (%) calculated for C 33 H 35 N 3 O 6: C 68.88; H, 6.24; N, 7.30; found: C 68.49; H, 6.29; N, 7.21.

Example 215 1- {4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} cyclopropanecarboxylic acid

To a solution of Example 214 (0.35 g, 0.61 mmol) in mL of CH 2 Cl 2 was added 2 mL of TFA. The yellow solution was stirred at room temperature for 4 hours, the reaction mixture was concentrated and the residue was overlaid with diethyl ether. 0.25 g (79% yield) of a white solid corresponding to the desired compound is obtained.

Melting point: 179-181 ’C,

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CHN Analysis (%) calculated for C ₂₉ H 7 N ₂ O _{3 6:} C, 66.22; H, 5.35; N, 7.77; found C 66.61; H, 5.40; N, 8.04.

Example 216

3-Benzyl-6-benzylsulfanyl-l-methyl-lH-quinazoline-2,4-dione

Step 1: 5-Iodo-2-methylaminobenzoic acid

To a solution of N-methylanthranilic acid (5.00 g, 3.31 mmol) in 30 mL acetic acid was added 60 mL H ₂ O followed by crystalline iodine (8.39 g, 3.31 mmol) in portions over 5 minutes. The reaction mixture was stirred at room temperature for 2 days. After 48 hours, the product was collected by filtration and washed with 30 mL of water. The mother liquors were concentrated to give an additional crop of product. 7.3 g; yield = 80%; of the desired product.

Melting point: 170-172 ° C;

mass spectrum (APCI +): m / z 276.0 (MH +).

Step 2: 3-Benzyl-6-iodo-1-methyl-1H-quinazoline-2,4-dione

To a mixture of the compound obtained in the previous step 1 (0.50 g, 1.9 mmol), isothiocyanate (0.236 g, 1.58 mmol) and CE ₃ CO ₂ Ag (0.838 g, 3.90 mmol) is slowly added Et ₃ N. Heat the reaction mixture at reflux for 1.5 hours. After cooling to room temperature, the silver sulfide was collected by filtration and the filtrates were concentrated. A brown oil is obtained which is chromatographed

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229 purified on silica gel (ethyl acetate / hexane: 20:80) to give

0.300 g (48.0%) of a white solid.

M.p .: 149-150 ° C;

mass spectrum (APCI +): m / z 391.0 (MH).

Step 3: 3-Benzyl-6-benzylsulfanyl-1-methyl-1H-quinazoline-2,4-dione

To a mixture of KHCO ₃ (0.009 g, 0.089 mmol), PPh ₃ (0.007 g, 0.027 mmol), n-BuLi (0.033 g, 0.089 mmol ·), Pd (OAc) ₂ (0.002 g, 0.009 mmol) after degassing with nitrogen add a solution of the compound from the previous step 2 (0.035 g, 0.089 mmol) and butylthiocarbamic acid S -benzyl ester (0.020 g, 0.089 mmol) in 5 mL dioxane over 5 min at room temperature. The brown solution was heated to 100 ° C overnight. After 24 hours, the reaction mixture was cooled to room temperature and diluted with 20 mL of ethyl acetate, filtered through diatomaceous earth, washed with water (2 x 5 mL) and finally concentrated to give a yellow oil. Overlaying with diethyl ether gave 0.025 g (yield: 72%) of a yellow solid corresponding to the desired compound.

Melting point: 117-118 ° C.

CHN analysis (%) calculated for C ₂₃ H ₂₀ N ₂ O ₂ S: C 69.66; H, 5.31; N, 7.06; found: C 69.26; H, 5.04; N, 6.93.

Example 217

3-Benzyl-1-methyl-6-phenylmethanesulfinyl-1H-quinazoline-2,4-dione

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230

To a solution of the compound of Example 216 (0.050 g, 0.129 mmol) in 9 mL of anhydrous CH 2 Cl 2 at -5 ° C was added m-chloroperbenzoic acid (0.029 g, 0.127 mmol) and the mixture was stirred at -5 ° C for 3 hours. The reaction was quenched with 20 mL of NaHCO 3 solution, the organic layer was separated and the aqueous extracted with CH 2 Cl 2 (2 x 20 mL), the combined organic layers were concentrated to give a yellow oil. g (yield: 33.7%) of a white solid corresponding to the desired compound:

M.p. 182-183 ° C.

CHN analysis (%) calculated for C 23 H 20 N 2 O 3 S: C 67.84; H, 5.03; N, 6.88; found: C 68.13; H, 4.86; N, 6.48.

Example 218

3-Benzyl-1-methyl-6-phenylmethanesulfonyl-IH-quinazoline-2,4-dione

To a solution of the compound of Example 216 (0.133 g, 0.342 mmol) in 25 mL anhydrous ΟΗ ₂ Ο ₁₂ was added m-chloroperbenzoic acid (0.153 g, 0.685 mmol) at -5 ° C. The mixture was stirred at -5 ° C for 5 min, then the ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction is quenched by the addition of 5 mL of saturated aqueous NaHCO ₃ solution. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic layers were concentrated to give a yellow oil which was overlaid with ethyl acetate to give 0.80 g (yield: 56%) of a pale yellow solid corresponding to the desired compound.

Melting point: 173-175 ° C.

CHN Analysis (%) calculated for C ₂₃ H ₂₀ N ₂ O4S: C, 64.73; H, 4.89; N, 6.56; found: C 64.34; H, 4.72; N, 6.18.

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Example 219 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid t-butoxycarbonylmethyl ester

MeO

To a solution of 0.40 g (0.84 mmol) of the compound of Example 35 in dimethylformamide (10 mL) was added 0.13 g of diisopropylethylamine (1.0 mmol) followed by 0.18 g of t-butylacetyl chloride (1.18 mmol). . The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue is diluted with ethyl acetate (20 mL) and the organic layer is washed with saturated aqueous sodium chloride solution (2 x 20 mL), dried over MgSO ₄ and chromatographed on silica gel (EtOAc / hexane) to give 0.11 g (yield 23%) of the desired compound.

Mass spectrum: m / z (APCI, AP +) 588.4 [M].

CHN analysis (%): C ₃₂ H ₃₃ N ₃ O ₈ .1.8H ₂ Calcd: C 61.97; H, 5.61;

N, 6.70; found: C 61.58; H, 5.61; N, 6.70.

Example 220

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethylbenzoic acid dimethylaminodimethylpropyl ester

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To a solution of 0.50 g (1.6 mmol) of the compound of Example 35 in dimethylformamide (20 mL) was added 0.39 g of EDAC HCl (2.1 mmol), 0.28 g of HOBT (2.1 mmol) and then 0.27 g of dimethylaminodimethylpropan-1-ol (2.1 mmol). The mixture was stirred at room temperature overnight, then water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (4 x 20 mL) and dried over MgSO 4. The crude product was dissolved in EtOAc / MeOH and saturated ethereal HCl was added. The mixture was concentrated and crystallized in EtOAc to give 0.49 g (43% yield) of the title compound.

Mass spectrum: m / z (APCI, AP +) 587.0 [M] ^T.

CHN analysis (%): C 33 H 35 N 4 OS. 1,0HC1.1,2H ₂ 0 requires: C, 61.40; H, 6.48; N, 8.68; found: C 61.01; H, 6.31; N, 8.99.

Example 221

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid dimethylaminomethylpropyl ester

To a solution of 0.50 g (1.6 mmol) of the compound of Example 35 in dimethylformamide (20 mL) was added 0.39 g of EDAC HCl (2.1 mmol),

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0.28 g HOBT (2.1 mmol) then 0.24 g dimethylaminomethylpropan-1-ol (2.1 mmol). The mixture was stirred at room temperature overnight, then water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (4 x 20 mL) and then dried over MgSO ₄ . The crude product was dissolved in EtOAcMeOH and saturated ethereal HCl was added. Concentration and crystallization in EtOAc gave 0.21 g (21% yield) of the title compound.

Mass Spectrum: m / z (APCI AP +) 573.2 [M] ⁺ .

CHN Analysis (%) C32H36N4O6.1,0HC1.0,4 8 H ₂ O Calcd: C, 62.22;

H, 6.19; N, 9.07; found: C 61.82; H, 6.00; N, 9.16.

Example 222

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-dimethylaminoethyl ester

To a solution of 0.73 g (1.5 mmol) of the compound of Example 35 in dimethylformamide (10 mL) was added 0.38 g EDAC HCl (2.0 mmol), 0.27 g HOBT (2.0 mmol) and then 0.18 g of dimethylaminopropan-1-ol (2.0 mmol). The mixture was stirred at room temperature overnight, then water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 20 mL) and dried over MgSO ₄ . The crude product was crystallized in EtOAc to give 0.49 g (60% yield) of the title compound.

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Mass spectrum: m / z (APCI, AP +) 545.3 [M] &lt; ^{+ &gt};.

CHN Analysis (%): C ₃ oH ₃₂ N ₄ O _p. 0.2 0 5 H ₂ O: C, 65.62; H, 5.97; N, 10.20; found: C 65.62; H, 5.92; N, 10.23.

Example 223

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid chloromethyl ester

To a solution of Example 35 (1.0 g, 2.1 mmol) in DMF (15 mL) was added diisopropylethylamine (0.47 g, 3.6 mmol) followed by chloroiodomethane (1.86 g, 10.5 mmol). The mixture was stirred overnight at room temperature, then diluted with ethyl acetate (20 mL), the organic layer was washed with water (1 x 10 mL), saturated aqueous sodium chloride solution (2 x 10 mL) and finally dried over MgSO ₄ . Crystallization in ether gave 0.29 g (26% yield) of the title compound.

Mass spectrum: m / z (APCI, AP +) 522.2 [M] ⁺ .

CHN analysis (%): C ₂₇ H ₂₄ ClN ₃ O 5 Calcd: C 62.13; H, 4.63; N, 8.05; found: C 62.08; H, 4.61; N, 7.95.

Example 224

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl 2-t-butoxycarbonylamino-3-methyl- (1-butanoyioxymethyl ester) ester ] benzoic acid

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MeO

Me

0 '| Γ ^Ν Τ ° ŕYWY γΑΑγΝ ^ ΑΑ iP:

To a solution of 0.39 g (0.75 mmol) of the compound of Example 223 in dimethylformamide (10 mL) was added 0.12 g of diisopropylethylamine (0.96 mmol) followed by 0.21 g of t-butoxycarbonylleucine 0.21 g (0). , 96 mmol). The mixture was stirred at 60-70 ° C overnight (12 h), then cooled and diluted with ethyl acetate (20 mL). The organic layer was washed with water (1 x 10 mL), 5% aqueous sodium bicarbonate (1 x 10 mL), saturated aqueous sodium chloride (1 x 10 mL) and finally dried over MgSO ₄ . The evaporation residue is chromatographed on silica gel (EtOAC / hexane) to give 0.14 g (25% yield) of the title compound.

Mass spectrum: m / z (APCI, AP +) 701.3 [M-Boc].

CHN Analysis (%) C ₃ H ₄ 7H42N ₁₀ O: C, 61.97; H, 5.61; N, 6.70;

found: C 61.58; H, 5.61; N, 6.70.

Example 225

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-amino-3-methylbutanoyloxymethyl ester hydrochloride

O O

To a solution of Example 224 (0.14 g, 0.19 mmol) in dioxane (10 mL) was added 1.0 M HCl in ether (10 mL). To

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Hydrogen chloride gas was then passed through the mixture for 2 min. The mixture was then stirred at room temperature for 90 min, concentrated and the residue overlaid with EtOAc. 0.039 g (30% yield) of the title compound is obtained.

Mass spectrum: m / z (APCI, AP +) 603.2 [M] &lt; ^{+ &gt};.

CHN analysis (%): C ₃₇ H ₄₂ N ₄ O 10 Calcd: C 61.97; H, 5.61; N, 6.70; found: C 61.58; H, 5.61; N, 6.70.

Example 226

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazoline-3- (2-t-butoxycarbonylamino-3-methylbutanoylamino) -3-methylbutanoyloxymethyl ester ylmethyl] benzoic acid

Step 1: 2- (2- t -Butoxycarbonylamino-3-methylbutanoylamino) -3-methylbutanoic acid methyl ester

To a solution of 1.3 g (5.9 mmol) of t-butoxycarbonylleucine in dimethylformamide (15 mL) was added 1.4 g of EDAC HCl (7.1 mmol), 0.95 g of HOBT (7.1 mmol), and then 1 1.0 g NH ₂ -Leu-OMe (5.9 mmol). The mixture was stirred at room temperature overnight, then water (20 mL) was added and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with 10% aqueous Na ₂ CO 3 (1 x 10 mL), saturated aqueous sodium chloride (2 x 20 mL), and then dried over MgSO ₄ . Crystallization in ether gave 1.05 g (53% yield) of the title compound.

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Mass spectrum: m / z (APCI, AP +) 331.2 [M] &lt; ^{+ &gt};.

CHN Analysis (%) C ₁₆ H ₃ oN ₂ 0 ₅ requires: C, 58.16; H, 9.15; N, 8.48;

found: C 58.32; H, 9.24; N, 8.51.

Step 2: 2- (2- t -butoxycarbonylamino-3-methylbutanoylamino) -3-methylbutanoic acid

To a solution of 0.4 g (1.2 mmol) of the compound obtained in the previous step 1 in 3: 1: 1 methanol / water / THF (10 mL) is added LiOH.H ₂ O (0.06 g; 1.44) mmol). The mixture was stirred at room temperature overnight, then partitioned between water (20 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous layer was acidified with 2M HCl solution. The product was extracted with EtOAc (2 x 20 mL), washed with a saturated aqueous sodium chloride solution (1 x 20 mL) and dried over MgSO ₄ . Crystallization in ether gave 0.22 g (58% yield) of the title compound.

Mass spectrum: m / z (APCI AP +) 317.2 [M] &lt; ^{+ &gt};.

CHN analysis C ₅ H 8 N ₂ C _2> 5 O: C, 56.94; H, 8.92; N, 8.85; found: C 56.72; H, 8.89; N, 8.64.

Step 3: 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazoline-3-2- (2-t-butoxycarbonylamino-3-methylbutanoylamino) -3-methylbutanoyloxymethyl ester -ylmethyl] benzoic acid

To a solution of 0.29 g (0.56 mmol) of the compound obtained in Example 223 in dimethylformamide (10 mL) was added 0.092 g of diisopropylethylamine (0.72 mmol) followed by 0.23 g of the compound obtained in the previous step 2 (0.72 mmol). mmol) and then a catalytic amount of NaI. The mixture was stirred overnight (18 h) at 50 ° C. It was then cooled, diluted with water and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed

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238 saturated aqueous sodium bicarbonate solution (1 x 10 mL), saturated aqueous sodium chloride solution (3 x 10 mL), and then dried over MgSO ₄ . Crystallization in EtOAc / hexane gave 0.27 g (63% yield) of the title compound.

Mass Spectrum: m / z (APCI, AP +) 800.4 [M-Boc] ’.

CHN analysis (%): C37H42N4O10 calculated: C 62.91; H, 6.41; N, 8.73;

found: C 62.59; H, 6.44; N, 8.39.

Example 227

4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] 2- (2-Amino-3-methylbutanoylamino) -3-methylbutanoyloxymethyl ester benzoic acid

MeO

ABOUT

ABOUT

To a solution of Example 226 in 0.25 g (0.31 mmol) in dioxane (10 mL) was added 1.0 M HCl in ether (10 mL). HCl gas was then introduced into the mixture for 2 min and the mixture was then stirred at room temperature for 90 min. The mixture was concentrated and overlaid with EtOAc to give 0.12 g (55% yield) of the title compound.

Mass Spectrum m / z (APCI AP +) 702.0 [M] ⁺ .

CHN analysis (%): C 37 H 43 N 5 O 9 Calcd: C 63.33; H, 6.18; N, 9.98;

found C 62.99; H, 6.06; N, 9.72.

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239

Examples 228 to 345

The following compounds were also obtained by the procedure of Example 168 and then by the procedure of Example 169:

3- [2- (4-Bromo-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine (2-methoxy-pyridin-4-ylmethyl) -amide 3- [2- (4-Fluoro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [6-carboxylic acid, 2-methoxy-pyridin-4-ylmethyl) -amide 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2- [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1, 3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide, 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1, 2,3-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-2,3-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo 1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide -1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methoxypyridine-4- 3- (3-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid ylmethyl) amide,

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240 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6- (2-methoxy-pyridin-4-ylmethyl) -amide 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine, carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide 3- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 6-carboxylic acid, 6-carboxylic acid, 2-methoxy-pyridin-4-ylmethyl) -amide; 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3-methoxypyridin-4-ylmethyl] amide 4-d] pyrimidine-6-carboxylic acid 3- (4-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [4-d] pyrimidine-β-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide [ 3,4-d] pyrimidine-6-carboxylic acid, 3- [2- (4-bromophenoxy) ethyl] -1-methyl-2,4-dioxc-1,2, (2-ethoxy-pyridin-4-ylmethyl) -amide, 3- [2- (4-Fluorophenoxy) ethyl] -1-methyl-2,4- (3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-ethoxy-pyridin-4-ylmethyl) -amide) dioxo-1,2,3,4-tetrahydropyrido-3,4-d] pyrimidine-6-carboxylic acid 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyridine-2-ethoxy-pyridin-4-ylmethyl) -amide 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4- b] pyrimidine-6-carboxylic acid, (2-ethoxypyridin-4-ylmethyl) amide d] pyrimidine-6-carboxylic acid,

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3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 241 (2-ethoxy-pyridin-4-ylmethyl) -amide 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo) -1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6 (2-ethoxy-pyridin-4-ylmethyl) -amide -carboxylic acid, 3- (3-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine- (2-ethoxy-pyridin-4-ylmethyl) -amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine, 6-carboxylic acid, (2-ethoxy-pyridin-4-ylmethyl) -amide 3- (3,4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4- d] -6-carboxylic acid, (2-ethoxy-pyridin-4-ylmethyl) -amide d] pyrimidine-6-carboxylic acid 3- (3-chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido (2-ethoxypyridin-4-ylmethyl) amide 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4- [3,4-d] pyrimidine-β-carboxylic acid, (2-ethoxy-pyridin-4-ylmethyl) -amide tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- (4-ethoxy-pyridin-4-ylmethyl) -amide -methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- [2- (pyridin-4-ylmethyl) amide] (4-bromophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid,

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242 3- [2- (4-Fluorophenoxy; ethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine- (pyridin-4-ylmethyl) amide 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4- (6-carboxylic acid), pyridin-4-ylmethyl) -amide d] pyrimidine-6-carboxylic acid 3- (4-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] (pyridin-4-ylmethyl) amide 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, pyridin-4-ylmethyl) amide 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-pyrimidine-6-carboxylic acid (pyridin-4-ylmethyl) amide 3- (3-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid, (pyridin-4-ylmethyl) -amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6, 6-carboxylic acid, (pyridin-4-ylmethyl) amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-t-carboxylic acid (pyridin-4-ylmethyl) amide 3- (3,4-Difluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid (pyridin-4-ylmethyl) -amide -tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid,

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243 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidin-6 (pyridin-4-ylmethyl) -amide 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6- (3-methoxybenzyl) amide-carboxylic acid 3- (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, carboxylic acid, (pyridin-4-ylmethyl) amide 3- [2- (4-Bromo-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] acid, 2-aminopyridin-4-ylmethyl) -amide 3- [2- (4-Fluorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2-aminopyridin-4-ylmethyl] amide] pyrimidine-6-carboxylic acid 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2- [3,4-d] pyrimidine-6-carboxylic acid, (2-aminopyridin-4-ylmethyl) -amide 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1, 3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-aminopyridin-4-ylmethyl) amide, 3- (4-br-2-aminopyridin-4-ylmethyl) -amide, 2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- (4-aminopyridin-4-ylmethyl) amide -fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid,

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244 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (2-aminopyridin-4-ylmethyl) amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6- (2-aminopyridin-4-ylmethyl) amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-aminopyridin-4-ylmethyl) amide -carboxylic acid, 3- (3,4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] (2-aminopyridin-4-ylmethyl) amide 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-tetrahydro-pyridin-4-ylmethyl] -amide, pyrimidine-6-carboxylic acid - (d) pyrimidine-6-carboxylic acid 3- (3-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, (2-aminopyridin-4-ylmethyl) amide] 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3-d] pyrimidine-6-carboxylic acid, (2-aminopyridin-4-ylmethyl) amide 3- [2- (4-d) pyrimidine-6-carboxylic acid, (6-methoxypyridin-3-ylmethyl) amide (4-bromophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (β-methoxypyridin-3-ylmethyl) 3- [2- (4-Fluorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid amide,

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245 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] (6-methoxy-pyridin-3-ylmethyl) -amide 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-methoxy-pyridin-3-ylmethyl) -amide 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4- b] pyrimidine-6-carboxylic acid, (6-methoxy-pyridin-3-ylmethyl) -amide; d] pyrimidine-6-carboxylic acid 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-fluoro-benzyl] -amide (6-methoxy-pyridin-3-ylmethyl) -amide - (d) pyrimidine-6-carboxylic acid 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, (6-methoxy-pyridin-3-ylmethyl) -amide]; 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3-b] pyrimidine-6-carboxylic acid, (6-methoxypyridin-3-ylmethyl) amide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [4-d] pyrimidine-6-carboxylic acid, (6-methoxypyridin-3-ylmethyl) amide [ 3,4-d] Pyrimidine-6-carboxylic acid, (6-Methoxy-pyridin-3-ylmethyl) -amide 3 - (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-methoxypyridin-3-ylmethyl) 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid amide,

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3- (3-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6- (6-methoxy-pyridin-3-ylmethyl) -amide 3- (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyridine-6-carboxylic acid, (6-methoxy-pyridin-3-ylmethyl) -amide 3- [2- (4-Bromo-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-a] -carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) -amide -d] pyrimidine-6-carboxylic acid 3- [2- (4-fluorophenoxy) ethyl-1-methyl-2,4-dioxo-1,2,3,4- (6-ethoxy-pyridin-3-ylmethyl) -amide 3- [2- (4-Chloro-phenoxy) -ethyl] -1-methyl-2,4-dioxo-1 (6-ethoxy-pyridin-3-ylethyl) -tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid; 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1, (6-ethoxy-pyridin-3-ylmethyl) -amide, 2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-2,3-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) -amide 1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid amide, (6-ethoxypyridin-3-ylmethyl) 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid amide,

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3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 247 (6-ethoxy-pyridin-3-ylmethyl) -amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidin-6- (6-ethoxy-pyridin-3-ylmethyl) -amide 3- (3,4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyxido [3,4-d] pyrimidine, carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) -amide 3- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 6-ethoxy-pyridin-3-ylmethyl] -amide; 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3-d] pyrimidine-6-carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) -amide 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [4-d] pyrimidine-6-carboxylic acid, (6-ethoxy-pyridin-3-ylmethyl) -amide [ 3,4-4] pyrimidine-5-carboxylic acid 3- [2- (4-bromophenoxy) ethyl-1-methyl-2,4-dioxo-1,2,3,4 (pyridin-3-ylmethyl) amide Tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- [2- (4-fluoro) -pyridin-3-ylmethyl) -amide (phenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- [2- (pyridin-3-ylmethyl) amide] 4-chlorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid,

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3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (pyridin-3-ylmethyl) amide, 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (pyridin-3-ylmethyl) amide, ( 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid pyridin-3-ylmethyl) amide, (pyridine) 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid -3-ylmethyl) amide, (pyridine- 3- (3-Bromo-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 3-ylmethyl) amide, (pyridine) 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid -3-ylmethyl) amide, (pyridine- 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 3-ylmethyl) amide, (pyridine) 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-ylmethyl) -amide 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4 rido [3,4-d] pyrimidine-6-carboxylic acid, pyridin-3-ylmethyl) amide -tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid,

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3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (pyridin-3-ylmethyl) amide, 3- [2- (4-Bromo-phenoxy) -ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine- (6-aminopyridin-3-ylmethyl) -amide 3- [2- (4-fluorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 6-carboxylic acid, 6-aminopyridin-3-ylmethyl) amide 4-d] pyrimidine-6-carboxylic acid 3- [2- (4-chlorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3, 6-aminopyridin-3-ylmethyl) amide 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3-4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-aminopyridin-3-ylmethyl) amide 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2, (6-aminopyridin-3-ylmethyl) amide, 4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-aminopyridin-3-ylmethyl) amide 3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (6-aminopyridin-3-ylmethyl) amide 3- ( 3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 3- (6-aminopyridin-3-ylmethyl) amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid,

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3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid (6-aminopyridin-3-ylmethyl) amide 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine- (6-aminopyridin-3-ylmethyl) amide, 3- (3-chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 6-aminopyridin-3-ylmethyl] amide; 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3-d] pyrimidine-6-carboxylic acid, (6-aminopyridin-3-ylmethyl) amide 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [4-d] pyrimidine-6-carboxylic acid, (6-aminopyridin-3-ylmethyl) amide [ 3,4-d] pyrimidine-6-carboxylic acid, 3- [2- (4-bromophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2, (2-methylaminopyridin-4-ylmethyl) amide, 3- [2- (4-Bromophenoxy) ethyl] -1-methyl-2,4- (3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, 2-methylaminopyridin-4-ylmethyl) amide dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid, ( 3- [2- (4-Chloro-phenoxy) -ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidin-6-methylaminopyridin-4-ylmethyl) -amide - carboxylic acid 3- (4-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] (2-methylaminopyridin-4-ylmethyl) amide pyrimidine-6-carboxylic acid,

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3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxy- (2-methylaminopyridin-4-ylmethyl) amide 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine- (2-methylaminopyridin-4-ylmethyl) -amide; 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] 6-carboxylic acid, (2-methylaminopyridin-4-ylmethyl) amide pyrimidine-6-carboxylic acid, 3- (3-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2-methyl-aminopyridin-4-yl · methyl] amide [ 3,4-d] pyrimidine-6-carboxylic acid 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4- (2-methylaminopyridin-4-ylmethyl) amide 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methylaminopyridin-4-ylmethyl) amide, 3- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid, (2-methylaminopyridin-4-ylmethyl) amide -l, 2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylate 3- (3-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine- (2-methylaminopyridin-4-ylmethyl) amide; 6-carboxylic acid, and 3- (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] (2-methylaminopyridin-4-ylmethyl) amide pyrimidine-6-carboxylic acid.

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252

Examples 345 to 461

The following compounds were prepared according to the procedure described in Example 131:

3- (3,4-Dichlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide, (pyridin-4-ylmethyl) 3- (3-Bromobenzyl) - (3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid amide), (pyridin-4-ylmethyl) amide 3- (3-Iodobenzyl) -1-methyl-2,4-dioxo 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 3- (3,4-dichlorobenzyl) -1-methyl-2,4-dioxo-1,2 (2-methoxy-pyridin-4-ylmethyl) -amide, 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline 3,4-tetahydroquinazoline-6-carboxylic acid, (2-methoxy-pyridin-4-ylmethyl) -amide 3- (3-chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6- (2-methoxy-pyridin-4-ylmethyl) -amide; 3- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide, (2- 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid methoxypyridin-4-ylmethyl) amide,

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253 3- (3-Iodobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) amide, (2-methoxypyridin-4) 3- (4-iodo-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid-1-methyl-methyl-amide, 3- (4-Hydroxy-pyridazin-4-ylmethyl) -amide 3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3,4-dichlorobenzyl) amide (1-hydroxypyridazin-4-ylmethyl) amide 1- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-hydroxypyridazin-4-ylmethyl) amide methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-fluorobenzyl) -1-methyl-2,4- (1-hydroxypyridazin-4-ylmethyl) amide 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 1-hydroxypyridazin-4-ylmethyl) amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazole, 4-tetrahydroquinazoline-6-carboxylic acid, (1-hydroxypyridazin-4-ylmethyl) amide 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, n-6-carboxylic acid, (1-hydroxypyridazin-4-ylmethyl) amide .

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254 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-oetrahydroquinazoline-6-carboxylic acid (1-hydroxypyridazin-4-ylmethyl) amide; 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-ylmethyl) amide, 3- (4-Methylaminopyridazin-4-ylmethyl) amide 3- 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methylaminopyridazin-4-ylmethyl) amide dichlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-chloro-4-fluorobenzyl) amide (1-methylaminopyridazin-4-ylmethyl) amide 1- (3-Fluorobenzyl) -1-methyl-2-l-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methylaminopyridazin-4-ylmethyl) amide 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1, 4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methylaminopyridazin-4-ylmethyl) amide, 3- (3-Bromobenzyl) -1-methyl-2,4-dio 2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methylaminopyridazin-4-ylmethyl) amide xo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3-l-methylaminopyridazin-4-ylmethyl amide 4-tetrahydroquinazoline-6-carboxylic acid,

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3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methylaminopyridazin-4) - (1-methylaminopyridazin-4-ylmethyl) amide 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methoxy-pyridin-4-ylmethyl) -amide 3- (4-bromo-benzyl) -amide 3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3,4-dichlorobenzyl) amide (1-methoxypyridazin-4-ylmethyl) amide 1- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methoxypyridazin-4-ylmethyl) amide methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-fluorobenzyl) -1-methyl-2,4- (1-methoxypyridazin-4-ylmethyl) amide 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methoxy-pyridazin-4-ylmethyl) -amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-4-tetrahydroquinazoline-6-carboxylic acid, (1-methoxypyridazin-4-ylmethyl) amide 3- (3-Iodobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methoxy-pyridazin-4-ylmethyl) -amide, quinazoline-6-carboxylic acid,

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256 1- (4-Fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methoxy-pyridin-4-ylmethyl) -amide, (1-methoxypyridazine) 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid -4-ylmethyl) amide, (1-Methoxy-pyridazin-4-ylmethyl) -amide 3 3- (4-Iodobenzyl) - (4-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methoxy-pyridazin-4-ylmethyl) -amide 3- (3,4-Difluorobenzyl) -1-methyl- (1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 2-hydroxypyridazin-4-ylmethyl) amide 3- (3,4-Dichlorobenzyl) -1-methyl-2,4-dioxo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-hydroxypyridazin-4-ylmethyl) amide -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1 (2-hydroxypyridazin-4-ylmethyl) amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-hydroxypyridazin-4-ylmethyl) amide 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid tetrahydroquinazoline-6-carboxylic acid, (2-hydroxy-pyridazin-4-ylmethyl) -amide,

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3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (2-hydroxypyridazine-4-ylmethyl) amide; 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-ylmethyl) amide, 3-Hydroxypyridazin-4-ylmethyl) amide 3- 3- (4-Bromobenzyl) -1- (4-chlorobenzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-chloro-pyridyl-4-ylmethyl) -amide) 3- (3,4-Difluorobenzyl) -1-methyl-2,4-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-aminopyridazin-4-ylmethyl) amide -Dioxo-1,2,3,4-tetrahydroquinazoline-5-carboxylic acid 3- (3,4-dichlorobenzyl) -1-methyl-2,4-dioxo-1 (1-aminopyridazin-4-ylmethyl) amide 3- (3-Chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-aminopyridazin-4-ylmethyl) amide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinone, 4-tetrahydroquinazoline-6-carboxylic acid, (1-aminopyridazin-4-ylmethyl) amide 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-amino-pyridazin-4-ylmethyl) -amide; acid,

01-L 699-93-Eng

3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-amino-pyridin-4-ylmethyl) -amide, (1-amino) r. 4- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid on-4-ylmethyl) amide, (1-aminopyridazine) 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid -4-ylmethyl) amide, (1-Aminopyridazin-4-ylmethyl) amide 3 3- (3,4-Difluorobenzyl) - (4-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-ethoxypyridazin-4-ylmethyl) amide 1- (3,4-Dichlorobenzyl) -1-methyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-ethoxypyridazin-4-ylmethyl) amide 2- (3-Chloro-4-fluorobenzyl) -1-methyl-2-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-ethoxypyridazin-4-ylmethyl) amide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2-4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-ethoxy-pyridazin-4-ylmethyl) -amide . 3- (3-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6, 3,4-tetrahydroquinazoline-6-carboxylic acid, (1-ethoxypyridazin-4-ylmethyl) amide -carboxylic acid, 3- (3-bromobenzyl) -1-methyl-2,4 (1-ethoxypyridazin-4-ylmethyl) amide

-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acids,

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259 3- (3-Iodobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-ethoxypyridazin-4-ylmethyl) amide, (1-ethoxypyridazine-4) 3- (4-Fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid-1-methyl-methyl-amide 3- (1-ethoxy-pyridazin-4-ylmethyl) -amide 3- ( 4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (4-bromobenzyl) -1- (1-ethoxypyridazin-4-ylmethyl) amide 3- (4-Iodobenzyl) -1-methyl-2,4-dioxo-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-ethoxy-pyridazin-4-ylmethyl) -amide -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 3- (3,4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2, (2-methylaminopyridazin-4-ylmethyl) amide, 3- (3,4-Dichlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline 3,4-tetrahydroquinazoline-6-carboxylic acid, (2-methylaminopyridazin-4-ylmethyl) amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazole-6-carboxylic acid, (2-methylaminopyridazin-4-ylmethyl) amide 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylaminopyridazin-4-ylmethyl) amine-6-carboxylic acid, 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylaminopyridazin-4-ylmethyl) amide,

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260 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylaminopyridazin-4-yl) -amide, (2-methylaminopyridazine-4) 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid-ylmethyl) amide 3- ((2-methylaminopyridazin-4-ylmethyl) amide) 3- ( 4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3,4-difluorobenzyl) amide - (1-methylpyridazin-4-ylmethyl) amide 3- (3,4-Dichlorobenzyl) -1-methyl-2 (1-aminopyridazin-4-ylmethyl) amide 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4- (4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 1-methyl-pyridazin-4-ylmethyl) -amide 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (1-methylpyridazin-4-ylmethyl) amide 3- (3-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-4-tetrahydroquinazoline-6-carboxylic acid (1-methyl-pyridazin-4-ylmethyl) -amide quinazoline-6-carboxylic acid 3- (3-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methylpyridazin-4-ylmethyl) amide,

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261

3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-methyl-pyridazin-4-ylmethyl) -amide, (1-methylpyridazine) 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid -4-ylmethyl) amide, (1-methylpyridazin-4-ylmethyl) amide 3 3- (3,4-Difluorobenzyl) - (4-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-ethoxypyridazin-4-ylmethyl) amide 1- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-ethoxypyridazin-4-ylmethyl) -amide 3- (3-fluorobenzyl) -1-methyl-2,4-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-ethoxy-pyridazin-4-yimethyl) -amide -dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2 (2-ethoxypyridazin-4-ylmethyl) amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6, 3,4-tetrahydroquinazoline-6-carboxylic acid, (2-ethoxypyridazin-4-ylmethyl) amide -ka 3- (3-iodobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-ethoxypyridazin-4-ylmethyl) amide, (2-ethoxypyridazine) 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid -4-ylmethyl) amide,

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3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-ethoxy-pyridazin-4-yimethyl) -amide, (2-etoxypyridazine-4) 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-ethoxypyridazin-4-ylmethyl) amide 3-ylmethyl) amide 3 3- (3,4-Difluorobenzyl) - (4-iodo-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-aminopyridazin-4-ylmethyl) -amide 1- (3,4-Dichlorobenzyl) -1-methyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-aminopyridazin-4-ylmethyl) amide 3- (3-chloro-4-fluorobenzyl) -1-methyl-2 (2-aminopyridazin-4-ylmethyl) amide -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2-4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-aminopyridazin-4-ylmethyl) amide 3- (3-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoic acid, 3,4-tetrahydroquinazoline-6-carboxylic acid, (2-aminopyridazin-4-ylmethyl) amide 3- (3-bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-aminopyridazin-4-ylmethyl) amide, 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-aminopyridazin-4-ylmethyl) amide,

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3- (4-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-cetrahydroquinazoline-6-carboxylic acid (2-aminopyridazin-4-ylmethyl) amide, (2-aminopyridazine-4) 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylpyridazin-4-ylmethyl) amide 3- (4-bromobenzyl) amide 3,4-Dichlorobenzyl-3,4-difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylpyridazin-4-ylmethyl) amide 1- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-methyl-pyridazin-4-ylmethyl) -amide methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-fluorobenzyl) -1-methyl-2,4- (2-methylpyridazin-4-ylmethyl) amide 3- (3-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, (2-methylpyridazin-4-ylmethyl) amide 3- (3-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6, 4-tetrahydroquinazoline-6-carboxylic acid, (2-methylpyridazin-4-ylmethyl) amide ka 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methylpyridazin-4-ylmethyl) amide,

01-1699-03 -C

3- (4-Chloro-benzyl) -1-methyl-2,4-cioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methyl-pyridin-4-ylmethyl) -amide; 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-ylmethyl) amide.

Example 462

In vitro activity evaluation of a compound of formula I according to the present invention

The ability of the compounds of formula (I) of the present invention to inhibit matrix metalloprotease 13 was evaluated by measuring their IC ₅₀ values (the concentration required for 50% inhibition of enzymatic activity) according to the procedure described below.

MMP13CD Thiopeptolide Test:

Proteolysis of the thiopeptolide substrate Ac-Pro-Leu-Gly-thiester-Leu-Leu-Gly-OEt is used as the primary model to determine IC ₅₀ values for MMP-13 inhibitors. 100 μΐ of reaction mixture contains 50 mM HEPES, 10 mM CaCl ₂ , pH 7.0 (room temperature), 1 mM 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB), 100 μΜ substrate, inhibitor v 2.0 % DMSO and 2.5 nM human catalytic enzyme domain collagenase-3. Inhibitors are tested from 100 μΜ to 0.5 nM. The change in absorbance at 405 nm is monitored on a microplate reader at room temperature continuously for 10 to 15 minutes. To derive ΙΟ ₅₀ values, control rate percentages for inhibited samples are recorded against inhibitor concentration.

01-1699-03 -C

265

Table 1:

Example IC ₅₀ (μΜ) Example IC50 (μΜ) 1 0,193 26 0,009 2 0, 183 27 1.7 3 0,021 28 0,017 4 1.87 29 0,003 5 0,366 30 0,026 6 0,049 31 0,157 7 0, 167 32 0, 6 8 1.32 33 0.75 9 0,005 34 0,004 10 0,057 35 0,001 11 2.25 36 0.028 12 0,042 37 0,029 13 0,012 38 0,031 14 0, 051 39 0,011 15 0.7 40 0,004 16 0,015 41 0,007 17 0,009 42 0.0025 18 0.01 43 1, 21 20 0,051 44 0,016 21 0.3 45 0,007 22 0,096 46 0,096 23 0,029 47 0,062 24 0,009 48 0,014 2 5 0,028

The test results presented in Table 1 show that the compounds of the present invention tested in the assay effectively inhibit matrix metalloprotease 13.

The procedure described above was also used to measure the activity of the compounds of the present invention against MMP1, MMP2, MMP3, MMP7, MMP9, MMP12 and MMP14. In this test IC50 values for these MMPs were often higher than 100 μΜ. These results show that the compounds of the present invention are selective MMP13 inhibitors.

01-1699-03-CE

6 6

Bibliographical references:

Montana J. and Baxter A., Current Opinion in Drug Discovery Developnent, 2000, 3 (4), 353-361.

Clark IM et al., Current Opinion in Anti-Inflanmatory Immunomodulatory Investigative Drugs, 2000, 2 (1), 16-25.

Claims (38)

1. A compound of formula I: where : R ¹ is a group selected from the group consisting of - a hydrogen atom, an amino group; - (C 1 -C 6) alkyl, (C 3 -C 6) alkenyl, (C 3 -C 6) alkynyl, (C 1 -C 6) monoalkylaminoalkyl, (C 1 -C 6) dialkylaminoalkyl (C 6 -C 6) aryl, aryl, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl, heterocyclic, and (C 3 -C 6) cycloalkylalkyl (C 1 -C 6) -alkyl wherein these groups are unsubstituted or substituted by one or more groups, which may be the same or different and are selected from the group consisting of amino, (C 1 -C 6) alkyl, cyano, (C 1 -C 6) haloalkyl, C (= O) OR ⁴ , OR ^4, and SR ⁴ wherein R ⁴ is hydrogen or (1-6C) alkyl, 01-1699-03 -C 268 O 1 is an oxygen atom, a sulfur atom or a group = N-R ', wherein R' is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a cyano group, X ¹ , X ² and X ³ are, independently of one another, a nitrogen atom or a group -CR ⁶ , wherein R ⁶ is a group selected from the group consisting of hydrogen, C 1 -C 6 alkyl, amino, C 1 -C 6 monoalkylamino carbon atoms, a dialkylamino group having 1 to 6 carbon atoms in each alkyl moiety, a hydroxyl group, a C1-6 alkoxy group and a halogen atom, provided that no more than two of X ¹ , X ² and X ³ are simultaneously nitrogen atom, Y is a group selected from oxygen, sulfur, -NH and -N-C 1 -C 6 -alkyl, Z is: - oxygen, sulfur, - or -NR ⁷ where R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl and - when Y is an oxygen atom, a sulfur atom, or an -N-alkyl group having 1 to 6 carbon atoms, Z is optionally a carbon atom which is unsubstituted or substituted by a group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, aryl, arylalkyl having 1 to 6 carbon atoms in the alkyl moiety, aromatic 01-1699-03-CE 269 or a non-aromatic heterocyclic group or cycloalkyl group, n is an integer from 1 to 8 inclusive, Z ¹ is -CR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen , amino, OR ⁴ , SR ⁴ or C (= O) OR ⁴ , wherein R ⁴ is hydrogen or (C 1 -C 6) alkyl, and if n is higher than or equal to two, the hydrocarbon chain Z ¹ optionally contains one or more multiple bonds. - and / or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, or a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms . - and if one of the carbon atoms of the hydrocarbon chain of Z ¹ is replaced by a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, the -C (= Y) -Z- group may be absent in the compound of the formula I, A is a group selected from the group consisting of: - an aromatic or non-aromatic, 5- or 6-membered monocycle containing from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and Ol · 1695-03-Ce 270 a cycle consisting of two aromatic or non -matic, 5- or 6-membered rings, which may be the same or different, containing 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, m is an integer from 0 to 7 inclusive, R group (s) R ² , which may be the same or different, is (are) selected from the group consisting of alkyl having 1 to 6 carbon atoms, halogen, -CN, '-NO ₂ , -SCF ₃ , -CF ₃ , -OCF ₃ , -NR ¹⁰ R ^{1: 1} , -OR ¹⁰ , -SR ^1C , -SOR ¹⁰ , -SO ² R ¹⁰ , - (CH ₂ ) kSO ₂ NR ¹⁰ R ^{1: L} , -X ⁵ (CH ₂ ) (= O) OR ¹⁰ , group - (CH ₂ ) _k C (= O) OR ¹⁰ , -X ⁵ (CH ₂ ) _k C (= O) NR ¹⁰ R ¹¹ , - (CH ₂ ) _k C (= O) NR ¹⁰ R ¹¹ , and -X ⁴ -R ^{L 2} , wherein: X ⁵ is selected from the group consisting of oxygen, sulfur optionally substituted with one or two oxygen atoms, and nitrogen substituted with hydrogen or C 1 -C 6 alkyl, - k is an integer from 0 to 3 inclusive, - R ¹⁰ and R ¹¹ , which may be the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, X ⁴ is a group selected from the group consisting of a direct bond, -CH ₂ -, an oxygen atom, a sulfur atom optionally substituted by one or more oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, - R ¹² is an aromatic or non-aromatic, hererocyclic or non-heterocyclic, 5- or 6-membered cyclic group, 01-1699-03-CE 271 which is unsubstituted or substituted by one or more groups, which may be the same or different, and are selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, hydroxyl and amino, and, when the ring is heterocyclic, contains 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; R ³ is a group selected from the group consisting of: - a hydrogen atom, - (C 1 -C 6) alkyl, (C 3 -C 6) alkenyl, (C 3 -C 6) alkynyl, which groups are unsubstituted or substituted by one or more groups which may be the same or different and are selected from the groups consisting of amino, cyano, group containing and SR may be the same or different, are hydrogen or alkyl of 1 to 6 carbon atoms, haloalkyl cycloalkyl -C (= 0) OR ^10, 1 to s group, OR group -C (= 0) NR ¹⁰ R ^n, 10 carbon atoms, wherein R ¹⁰ and R ^11, which - and a group of the formula wherein p is an integer from 0 to 8 inclusive, Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, 01-1699-03 -C 272 haloalkyl having 1 to 6 carbon atoms, halogen, amino, buy on OR ⁴ , SR ^4, and -C (= O) OR ⁴ , where R ⁴ is hydrogen or an alkyl group containing 1 to ⁴ carbon atoms; up to 6 carbon atoms, and - if p is greater than or equal to two, the hydrocarbon chain Z ² optionally contains one or more multiple bonds, - and / or the carbon atoms in the Z ² hydrocarbon chain may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, or group, B is a group selected from a group consisting of: - an aromatic or non-aromatic 5- or 6-membered monocycle containing 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and a bicyclic consisting of two aromatic or non-aromatic, 5- or 6-membered rings which may be the same or different, containing 0 to 4 from nitrogen, oxygen and sulfur, q is an integer from 0 to 7 inclusive, the group (s) R ⁵ , which may be the same or different, is selected from the group consisting of an alkyl group having 1 to 6 atoms carbon, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ^i: R ¹⁰ , -N (R ¹⁵ ) C (= O) R ¹⁵ - N (SO ₂ R ¹³ ) 2 / -OR -SO 2 N (R ¹⁵ ) group (CRN k ² NR ¹⁶ R ¹⁷ , group - (CH ₂ ) _k NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO ₂ R ¹⁶ ,, -S (O) _k i R ¹⁵ , group - (CH ₂ ) _to SO-NR ¹⁵ R ¹⁶ with Kuoina 01-1699-03-CE 273 ⁷ -X (CH 2) k C (= 0) OR ^15, - (CH 2) _k C (= 0) OR ^15, -C (= 0) 0- (CH2) ^ls k2NR ¹⁵ R, -C (= O) (CH 2) _{k 2} C (= O) OR ¹⁵ , -X ⁷ (CH 2) k C (= O) NR ¹⁵ R ¹⁵ , - (CH 2) _k C (= O) NR ¹⁵ R ¹⁶ , group R ¹⁹ -C (= 0) OR ^15, -X ^p R ^20, and -C (= 0) -R ²¹ -NR ¹⁵ R ^g, wherein - X ⁷ is selected from oxygen, sulfur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or C 1 -C 8 alkyl, - k is an integer from 0 to 3 inclusive, - kl is an integer from 0 to 2 inclusive, - k2 is an integer of 1 to 4 inclusive, - R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, - R ¹⁸ is selected from the group consisting of alkyl having 1 to 6 carbon atoms, R ²¹ -NR ¹⁵ R ^16, R ²¹ -NR ¹⁵ C (= 0) R ²¹ R ^17, -NR ^{1 S} , and -C (= O) OR ²¹ -NR ¹⁵ R ¹⁸ k wherein R ²¹ is a linear or branched alkylene group having 1 to 6 carbon atoms, and R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above, - R ¹⁹ is a cycloalkyl group having 3 to 6 carbon atoms, - X ⁶ is selected from the group consisting of a direct bond, -CH ₂ -, an oxygen atom, a sulfur atom optionally substituted by one or two oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, 01-1699-03 -C 274 - R ^ZJ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of alkyl having 1 to 6 carbon atoms, atom halogen, hydroxyl, oxo, cyano, tetrazole, amino, and -C (= O) OR ⁴ , where R ⁴ is hydrogen or (C 1 -C 6) alkyl, and if it is a heterocyclic ring it contains 1 to 6 4 heteroatoms selected from nitrogen, oxygen and sulfur, with the proviso that when X ¹ is a nitrogen atom, X ² may not be substituted by a methyl or NH-CH ₃ group or its racemic forms, its isomers, its N oxides and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein R ¹ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl or C 1 -C 6 cycloalkylalkyl of 3 to 6 carbon atoms, W is an oxygen atom or a sulfur atom, X ¹ is a nitrogen atom or a group -CR ⁶ wherein R ⁶ is a hydrogen atom, X ² and X ^J are each -CR ⁶ wherein R ⁶ is hydrogen, Y is an oxygen atom, Z is an oxygen atom or a group -NR ⁷ wherein R 'is a hydrogen atom, 01-1699-03-CE 275 optionally its racemic forms, its isomers, its N-oxides, and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein n is an integer from 1 to 6 inclusive, Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ is hydrogen and R ⁹ is hydrogen or methyl, and - if n is greater than or equal to 2, the hydrocarbon chain of Z ¹ optionally contains a double bond, - or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen or sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, A is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, piperidyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, benzofurazanyl, 2,1, 3-benzothiadiazolyl and indolyl, m is an integer from 0 to 7 inclusive, the group (s) R ² which may be the same or different is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ¹⁰ R ^n, -OR ^10, -SR ^10, -SO 2 R ¹⁰ group, - (CH 2) _a SO ₂ NR ¹⁰ R ¹¹ , X ⁵ (CH 2) k C (= O) OR ¹³ , - (CH 2) _k C (= O) OR ¹⁰ , X ⁵ (CH 2) k C (= O) NR ¹⁰ R ¹¹ , - (CH 2) group ) _to C (= O) NR ¹⁰ R ¹¹ and -X ⁴ -R ¹² where: X ⁵ is an oxygen atom, a sulfur atom or an NH group, 01-1699-03 -C 276 k is an integer from 0 to 3 inclusive, and R ¹¹ , which are the same or different, is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, X ⁴ is -CH ₂ -, or an oxygen atom, R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, halogen, hydroxyl and amino, or its racemic forms , isomers, N-oxides thereof, and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a group of the formula: where p is an integer from 0 to 3 inclusive, Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, methyl or phenyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ² or contains one double bond, - or one of the carbon atoms in the Z ² hydrocarbon chain may be replaced by an oxygen atom, a sulfur atom which is 01-1699-03-CE 277 unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, or a carbonyl group, B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl a group, a naphthyl group and an indolyl group, q is an integer from 0 to 3 inclusive; the group (s) R ⁵ , which may be the same or different, is (are) selected from the group consisting of alkyl having 1 to 6 carbon atoms, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO 2 R ^16, -N (SO 2 R ¹⁵⁾ 2, -OR ^13, -S (O) Kir ^15, a group -SO 2 N (R ¹⁵⁾ (CH 2) _{k 2} NR ¹⁶ R ^17, - (CH 2) R ¹⁵ kSO2NR ¹⁶ , -X ⁷ (CH 2) k C (= O) OR ¹⁵ , - (CH 2) k C (= O) OR ¹⁵ , -C (= O) O- (CH 2) _{k 2} NR ¹⁵ R ¹⁶ , - X ⁷ (CH ₂ ) _to C (= O) NR ¹⁵ R ¹⁵ and a group - (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ where - X 'is a group selected from oxygen, sulfur or NH, - k is an integer from 0 to 3 inclusive, - kl is an integer from 0 to 2 inclusive, k2 is an integer from 1 to 4 inclusive, 01-1699-03 -C 278 - R ^lj, Pn 'and R ^1' which may be the same or different, are selected from hydrogen or alkyl having 1 to 6 carbon atoms, optionally, the racemic forms thereof, isomers thereof, N-oxides and pharmaceutically acceptable salts thereof . A compound of formula I according to claim 1, wherein R ¹ is selected from the group consisting of: a hydrogen atom, an amino group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl group having 3 to 6 carbon atoms, a monoalkylaminoalkyl group having 1 to C atoms in each alkyl moiety (C 1 -C 6) -alkyl, aryl, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl, heterocyclic, and (C 3 -C 6) C 1 -C 6 -alkyl, wherein these groups are unsubstituted or substituted by one or more; a plurality of groups, which may be the same or different, selected from the group consisting of alkyl having 1 to 6 carbon atoms, cyano, haloalkyl having 1 to 6 carbon atoms, -C (= O) OR ⁴ , OR ^4, and SR ⁴ wherein R ⁴ is vo C 1-6 alkyl or C 1-6 alkyl; W is an oxygen atom, a sulfur atom or a group = N-R ', wherein R' is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a cyano group, 01-1699-03-CE 279 X ¹ is a nitrogen atom or a group -CR ⁵ wherein R ⁵ is a hydrogen atom, X ² and X ³ are independently -CR ⁵ , wherein R ⁶ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, amino, hydroxyl, and halogen, Y is an oxygen atom, Z is an oxygen atom or a group -NR ⁷ , wherein R ⁷ is a group selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, n is an integer of 1 to 6 inclusive, Z ¹ is -CR ^and R ⁹ , wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and hydroxyl, and when n is an integer above or is equal to 2, the hydrocarbon chain of Z ¹ optionally contains one or more multiple bonds, - or one of the carbon atoms in the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, or a nitrogen atom which is unsubstituted or substituted by an alkyl group containing 1 to 6 carbon atoms, A is a group selected from the group consisting of phenyl, pyriayl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl 01-1699-03-CE 280, benzofurazanyl, 2,1,3-benzothiadiazolyl, and indolyl, m is an integer from 0 to 3 inclusive, the group (s) ^R2, which may be the same or different, is (are) selected from the group of alkyl having 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ¹⁰ R ^{and l,} -OR ^10, -SR ^10, -SO 2 R ¹⁰ group , - (CH 2) k SO ² NR ¹⁰ R ¹¹ , -X ⁵ (CH 2) _{k to} C - (= O) OR ¹⁰ , - (CH 2) k C (= O) OR ¹⁰ , -X ⁵ (CH 2) _{k to} (= O) NR ¹⁰ R ¹¹ , - (CH ₂ ) _{k to} C (= O) NR ¹⁰ R ^11, and -X ⁴ -R ¹² , where: X ⁵ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive, R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, X ⁴ is -CH ₂ -, or an oxygen atom, R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, halogen and hydroxyl, R ³ is a group selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and a group of the formula 01-1699-03-CE 281 where p is an integer from 0 to 6 inclusive, Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are each independently hydrogen, C 1 -C 6 alkyl, and hydroxyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ^{2 is} optionally Contains one or more multiple bonds - or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,3,3-benzothiadiazolyl, benzofurazanyl a group, a naphthyl group and an indolyl group, q is an integer from 0 to 3 inclusive, the group (s) R ⁵ which may be the same or different is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, CN, N0 _2, CF _3, OCF ₃ group, a - (CH _{2) a} NR ¹⁵ R ^ls, -N (R ¹⁵⁾ C (= 0) ^R16, N ( R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S (O) kiR ¹⁵ , -SO ² N (R ¹⁵⁾ ) (CH 2) _{k 2} NR ¹⁶ R ¹⁷ , - (CH ₂ ) _k SO ₂ NR ¹⁵ R ¹⁵ , -X ⁷ (CH 2) k C (= O) OR ¹⁵ , - (CH 2) _k C (= 0) OR ^15, -C (= 0) 0 ~ - (CH _{2)> 2} NR ¹⁵ R ^{1 S, 7} -X (CH _{2) k} C (= 0) NR ¹⁵ R ¹⁶ group, - (CH ₂ ) _: -C (= O) NR ¹⁵ R ¹⁶ and -X ^with -R ²⁰ where 01-1699-03 -C 282 X 'is a group selected from oxygen, sulfur or NH, - k is an integer from 0 to 3 inclusive, - kl is an integer from 0 to 2 inclusive, - k2 is an integer of 1 to 4 inclusive, - R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, - X ⁵ is a group selected from the group consisting of a single bond, -CH ₂ -, an oxygen atom or a sulfur atom optionally substituted by one or two oxygen atoms, - R ²⁰ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, atom halogen, hydroxyl and amino, and when the ring is heterocyclic, contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally its racemic form, its isomers, its N-oxides, and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein R ¹ is selected from the group consisting of hydrogen, a monoalkylaminoalkyl group containing, in each alkyl moiety, 6-carbon atoms, a di-alkylaminoalkyl group containing 1 to 6 carbon atoms in each alkyl moiety, an alkyl group containing 1 to 6 carbon atoms, and an alkenyl group containing 01-1699-03-CE 283 (C 3 -C 6) alkynyl, (C 3 -C 6) alkynyl, (C 1 -C 6) aryl, (C 1 -C 6) arylalkyl, and (C 3 -C 6) cycloalkylalkyl (C 1 -C 6) alkyl, W is an oxygen atom or a sulfur atom, X ¹ is nitrogen or -CH, X ² and X ³ are -CH, Y is selected from the group consisting of oxygen, sulfur, -NH, and -N-alkyl of 1 to 6 carbon atoms, Z is O or -NH, n is an integer from 1 to 3 inclusive, Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxyl; and - if n is greater than or equal to two, the hydrocarbon chain Z ¹ optionally contains one double bond, - or one of the carbon atoms of the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two carbon atoms, or an -NH group, A is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl 01-1699-03 -C 284 group, 2,1,3-benzothiadiazolyl group, benzofurazanyl group, naphthyl group and indolyl group, m is an integer from 0 to 3 inclusive, the group (s) R ² , which may be the same or different, is (are) selected from the group consisting of alkyl having 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ¹⁰ R ^n, -OR ^10, -SR ^10, -SO 2 R group ¹⁰ , - (CH 2) _k SO ₂ NR ¹⁰ R ⁱⁱ , -X ⁵ (CH ₂ ) _{k to} C - (= O) OR ¹⁰ , - (CH 2) k C (= O) OR ¹⁰ , -X ⁵ (CH 2) _k C (= 0) NR ¹⁰ R ^11, - (CH _{2) k} C (= 0) NR ¹⁰ R ^n, and -X ⁴ -R ¹² wherein: X ⁵ is an oxygen atom, a sulfur atom or an NH group, k is an integer from 0 to 3 inclusive, R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, X ⁴ is -CH ₂ -, or an oxygen atom, R ¹² is a phenyl group which is unsubstituted or substituted by one or more groups, which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, halogen and hydroxyl, R ³ is a group selected from a methyl group and a group of the formula: where p is an integer from 0 to 3 inclusive, 01-1699-03-CE 285 Z ² is -CR ¹³ R ¹⁴ , wherein PC ³ and R ¹⁴ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and hydroxyl, and when p is greater than or equal to 2 , the hydrocarbon chain Z ² optionally contains one double bond, - or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, B is a group selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, 1,3-benzodioxolyl, benzodioxinyl, benzothienyl, benzofuryl, 2,1,3-benzothiadiazolyl, benzofurazanyl a group, naphthyl and indolyl, q is an integer from 0 to 3 inclusive, the group (s) R ⁵ which may be the same or different is (are) selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, halogen, CN, NO ₂ , CF 3, OCF 3, - (CH ₂ ) _to NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁵ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S (O) kiR ¹⁵ , -SO ² N (R ¹⁵ ) (CH 2) ) _k2 NR ¹⁶ R ¹⁷ , - (CH ₂ ) _k SO ₂ NR ¹⁵ R ¹⁶ , -X ⁷ (CH 2) k C (= O) OR ¹⁵ , - (CH 2) _k C (= O) OR ¹⁵ , -C (= O) O- (CH ₂ ) _{k 2} NR ¹⁵ R ^16, -X ⁷ (CH _{2) k} C (= 0) NR ¹⁵ R ^{1 S} group, - (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ and -X ^with -R ²⁰ where 01-1699-03-CE 286 X 'is a group selected from oxygen, sulfur or NH, - k is an integer from 0 to 3 inclusive, - ki is an integer from 0 to 2 inclusive, - k2 is an integer of 1 to 4 inclusive, - R ^15, R ¹⁶ and R ^{1 7,} which may be the same or different, are selected from hydrogen or alkyl having 1 to 6 carbon atoms, - X ⁶ is a group selected from the group consisting of a single bond, -CH ₂ -, an oxygen atom or a sulfur atom optionally substituted by one or two oxygen atoms, - R ²⁰ is an aromatic or non-aromatic, heterocyclic or non-heterocyclic, five or six membered ring which is unsubstituted or substituted by one or more groups which may be the same or different, selected from the group consisting of C 1 -C 6 alkyl, atom halogen, hydroxyl and amino, and when the ring is heterocyclic, contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally its racemic form, its isomers, its N-oxides, and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein R ¹ is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 1 -C 6 arylalkyl, C 3 -C 6 cycloalkylalkyl C 1 -C 6 alkyl . 01-1699-03 -C 287 W is an oxygen atom, 1 2 3 X is -CH or N and X and X are each -CH Y is an oxygen atom, Z is oxygen or -NH, n is an integer from 1 to 3 inclusive, Z ¹ is -CR ⁸ R ⁹ wherein R ⁸ and R ⁹ are each independently selected from hydrogen and methyl; and - if n is greater than or equal to two, the hydrocarbon chain Z ¹ optionally contains one double bond, - or one of the carbon atoms of the hydrocarbon chain of Z ¹ may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two carbon atoms, or an -NH group, A is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, and 1,3-benzodioxolyl, m is an integer from 0 to 3 inclusive, the group (s) ^R2, which may be the same or different, it is (are) selected from the group consisting of alkyl having 1 to 6 carbon atoms, halogen, -CN, -CF _3, -OCF _3, -NR ^{1 O U} R, -OR ¹⁰ , -SR ¹⁰ , -SO ² R ¹⁰ , - (CH 2) k SO 4 R ¹¹ R ¹¹ , -X ⁵ (CH ₂ ) _{k to} C (= O) -OR ¹⁰ , - (CH 2) k C (= 0) OR ^10, -X ⁵ (CH 2) _k C (= 0) NR ¹⁰ R ¹¹ and - (CH _{2) k} C (= 0) NR ^{1 O} R ^U, wherein: X ⁵ is an oxygen atom, a sulfur atom or an NH group, Ο ± -1699-0 j-Ce k is an integer from 0 to 3 inclusive, R ¹⁰ and R ¹¹ , which are the same or different, are selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, R ³ is a group of the formula wherein p is an integer from 0 to 3 inclusive, Z ² is -CR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are independently selected from hydrogen and methyl, and when p is greater than or equal to 2, the hydrocarbon chain of Z ² optionally contains one double bond, - or one of the carbon atoms of the hydrocarbon chain Z ² may be replaced by an oxygen atom, a sulfur atom which is unsubstituted or substituted by one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted by an alkyl group having 1 to 6 carbon atoms, B is selected from the group consisting of phenyl, pyridyl, thienyl, imidazolyl, furyl, and 1,3-benzodioxolyl, q is an integer from 0 to 3 inclusive, the group (s) ^R5, which may be same or different, is (are) selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, CN, NO ₂ , 01-1699-03 -C 289 CF ₃ , OCF ₃ , - (CH ₂ ) _k NR ¹⁵ R ¹⁶ , -N (R ¹⁵ ) C (= O) R ¹⁶ , -N (R ¹⁵ ) C (= O) OR ¹⁶ , -N (R ¹⁵ ) SO ² R ¹⁶ , -N (SO 2 R ¹⁵ ) 2, -OR ¹⁵ , -S (O) kiR ¹⁵ , -SO ² N (R ¹⁵ ) (CH 2) _{k 2} NR ¹⁶ R ¹⁷ , - (CH ₂ ) _k SO ₂ NR ¹⁵ R ¹⁶ , -X ⁷ (CH 2) k C (= O) OR ¹⁵ , - (CH 2) _k C (= O) OR ¹⁵ , -C (= 0) O- (CH ₂ ) _{k 2} NR ¹⁵ R ¹⁶ , -X ⁷ (CH ₂ ) _k C (= O) NR ¹⁵ R ^16, and - (CH ₂ ) _k C (= O) NR ¹⁵ R ¹⁶ where X ⁷ is a group selected from an oxygen atom, a sulfur atom. or NH, - k is an integer from 0 to 3 inclusive, - kl is an integer from 0 to 2 inclusive, - k2 is an integer of 1 to 4 inclusive, R ¹⁵ , R ¹⁶ and R ¹⁷ , which may be the same or different, are selected from a hydrogen atom or a C 1 -C 6 alkyl group, optionally its racemic form, its isomers, its N-oxides and its pharmaceutically acceptable salts. A compound of formula I according to claim 1, wherein R ¹ is a hydrogen atom or a C 1 -C 6 alkyl group, optionally its racemic forms, its isomers, its N-oxides, and its pharmaceutically acceptable salts. A compound of formula I according to claim 1, wherein W is an oxygen atom, Y is an oxygen atom, 01-1695-03 -C 290 Z is NH, Z ¹ is a methylene group and n is equal to 1, optionally its racemic forms, its isomers, the pharmaceutically acceptable salts. 10. A compound of formula I according to claim 1 X ¹ is -CH or N, and X ² and X ³ are each -CH, optionally its racemic forms, isomers, pharmaceutically acceptable salts thereof. 11. A compound of formula I according to claim 1 X ¹ and X ³ are each -CH a X ² is -CH or a nitrogen atom, optionally its racemic forms, isomers thereof, a pharmaceutically acceptable salt. 12. A compound of formula I according to claim 1 X ¹ and X ³ are each -CH a X ² is a nitrogen atom, optionally its racemic forms, its isomers, pharmaceutically acceptable salts. 13. A compound of formula I according to claim 1 A is a group selected from the group consisting of pyridyl, 1,3-benzodioxolyl furazanyl, its N-oxides and claim 1 thereof, wherein its N-oxides and claim 1, wherein its N-oxides and claim 1, wherein: the N-oxides thereof; and claim 1, wherein the phenyl group, and the benzo01-1699-03-C6 group 291 m is equal to 0 or 1 a R ² is selected from the group consisting of C 1 -C 6 alkoxy, hydroxyl, halogen and C 1 -C 6 thioalkoxy, optionally its racemic forms, its isomers, its N-oxides and its pharmaceutically acceptable salts. A compound of formula I according to claim 1, wherein R ³ is a group of the formula: where: p is equal to 1, Z ² is a methylene group, B is a group selected from the group consisting of phenyl, pyridyl, 1,3-benzodioxolyl and benzofurazanyl, q is an integer from 0 to 2 inclusive, and R ⁵ is a group selected from halogen, CN , - (CH 2) r NR ¹⁵ R ¹⁶ , -S (O) kl R ¹⁵ , - (CH 2) k SO ² NR ¹⁵ R ¹⁶ , - (CH 2) _k C (= O) OR ¹⁵ , -X ⁶ -R ²⁰ and - (CH ₂ ) _k C (O) NR ¹⁵ R ¹⁶ wherein k is an integer from 0 to 1 inclusive, kl is an integer from 0 to 2 inclusive, 01-1699-03 -C 292 R 1 and R ¹⁶ , which may be the same or different, are selected from the group consisting of hydrogen and alkyl containing 1 to 6 carbon atoms, X ° is a single bond, R ²⁰ is a five membered heterocyclic ring containing 3 to 4 heteroatoms selected from oxygen and nitrogen and optionally substituted with methyl or oxo, optionally its racemic forms, isomers, N-oxides thereof, and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1 which is: 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-pyridylmethyl) amide 3-benzyl-2,4-dioxo-1,2-benzylamide 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid tetrahydroquinazoline-6-carboxylic acid (2-thienylmethyl) amide 3-Benzo [1,3] dioxol-5-ylmethyl) amide 3 3-Benzyl-2,4-dioxo-1,2,3,4-trahydroquinazoline-6-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (3-pyridylmethyl) -amide -carboxylic acid 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-chlorobenzylamide 01-1699-03 -C 293 3-Benzyl-1-methyl-2-3-benzyl-2,4-diaxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methyl-benzylamino-benzo [1,3] dioxol-5-ylmethyl) -amide 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid benzylamide, 4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid, methyl -4 - ({[1- (3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-6-yl) methanoyl] amino} methyl) benzoate 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxy-3-methoxybenzylamide 3-Benzyl-1-methyl-2,4-dioxo-4-methoxybenzylamide 3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (4-pyridylmethyl) amide -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide 1-methyl-2,4-dioxo-3-phenethyl-1,2,3, 3- (4-Methoxybenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide 3- (4-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide (benzo [1,3] dioxol-5-ylmethyl) amide 3 - (1-naphth-1-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 01-1699-03 -C 294 Benzylamide 2-2,4-dioxo-3- (pyrid-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) amide 2, 4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzylamide 1-methyl-2,4-dioxo-3- (thien-2-ylmethyl) -1 2,4-Dioxo-3- (thien-2-ylmethyl) -1,2,3, 2,4,4-tetrahydro-quinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide, 1-methyl-2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4- (4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide) 3- (4-Chlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide (benzo 3- (4-Chlorobenzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid [1,3] dioxol-5-ylmethyl) amide [benzo [1,3] Dioxol-5-ylmethyl) amide Benzo [1] 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide , 3] dioxol-5-ylmethyl) -2,4-dioxo-2,3,4-t 3- (Benzo [1,3] dioxol-5-ylmethyl) -1-methyl-2,4-dioxo-1-etrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide, 2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide 3-benzyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline- 6-carboxylic acid 01-1699-03 -C 295 3-Benzyl-1-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide (benzo [1,3] 3-Benzyl-1-isobutyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid dioxol-5-ylmethyl) amide (Benzo [1,3] dioxol-5-ylmethyl) amide 1 methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-methyl dihydro-2H-quinazolin-3-ylmethyl benzoate 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (benzo [1,3] dioxol-5-ylmethyl) 1-methyl-2,4-dioxo-3 - ((E) -3-phenylalyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid amide benzyl-3-benzyl-2,4-dioxo-1 Benzyl 3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate, 2,3,4-tetrahydroquinazoline-6-carboxylate 4-pyridylmethyl-3-benzyl-2,4-dioxo-2,3,4-tetrahydrochinazo1in-6-carboxylate 4-pyridylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate benzo [1,3] dioxol-5-ylmethyl-3-benzyl-2,4 dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate benzo [1,3] dioxol-5-ylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4- tetranydrochinazolin-6-carboxylate 01-1699-03 -C 296 benzyl-1-benzyl-2,4-dioxo-3-pyrid-4-ylmethyl-1,2,3,4-theorahydroquinazoline-6-carboxylate 4-pyridylmethyl-2,4-dioxo-3- (thienyl-2-ylmethyl) -1,2,4,4-tetrahydroquinazoline-6-carboxylate 4-pyridylmethyl-3- (benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate benzyl-3-benzyl-2,4-dioxo-1 2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylate 4-Pyridylmethyl-3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylate (Benzo [1,3] dioxol-5-ylmethyl) amide 3 -benzyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4- [6- (4-hydroxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydr-2H-quinazolin-3-ylmethyl] benzoic acid 3- (4-Dimethylcarbamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- (4-methylcarbamoylbenzyl) -2,4-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (2-pyrrol-1-ylethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (2-prop-2-ynyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 01-1699-03 -C 297 1-methyl-3- (3-methylbut-2-enyl) -2,4-dioxo-1,2,3,4-tetrahydrocninazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (pyridin-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3-Carbamoylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (pyridin-3-ylmethyl-) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1,1-Methyl-3- (1-methylpiperidin-3-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (2-Methoxyethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3-Cyclopropylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- (2-morpholin-4-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 01-1699-0 3-Ce 298 1-methyl-2,4, dioxo-3- (3-phenylpropyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- [2- (4-Diethylaminophenyl) -2-oxoethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide ethyl [6- (4- methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] acetate 3- (2-Hydroxyethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydrocninazoline-6-carboxylic acid 4-methoxybenzylamide methyl-3- [6- (4-methoxybenzylcarbamoyl) -1- methyl 2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] propionate 3- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] propionic acid ethyl 4- [6- (4-methoxybenzylcarbamoyl) - l-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-yl] butyrate 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] butanoic acid methyl {4- [6- (4-methoxybenzylcarbamoyl)] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} acetate (4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-) 1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} acetic acid 3- (4-Dimethylcarbamoylmethylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 01-1699-03-CE 299 1-Methyl-2,4, dioxo-3 - [(E) -3- (pyridin-3-yl) allyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3 - [(E) -3- (pyridin-4-yl) allyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (4-sulfamoylbenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Methanesulfonylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- [4- (2-Dimethylaminoethylsulfamoyl) benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl-3- [6- (4-methoxybenzylcarbamoyl) -1- methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (E) -methyl 4- [6- (4-methoxybenzylcarbamoyl) 1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] but-2-enoate 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl] but-2-enoic acid methyl-5- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] furan-2-carboxylate 01-1699-03 -C 300 5- (6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl) furan-2-carboxylic acid methyl-5- [6- (4- benzylcarbamoyl) -1-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] -thiophene-2-carboxylate 5- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] thiophene-2-carboxylic acid 1-Methyl-3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Aminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Dimethylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Acetylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- [4- (N, N-Methylsulfonylamino) -benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (Benzofurazan-5-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- [2- (4-Fluorophenoxy) ethyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (2-Benzenesulfonylethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Fluoro-4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 01-1699-03-CE 301 1-Methyl-2,4-dioxo-3- [4- (2H-tetrazol-5-yl) benzyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6- 4-methoxybenzylamide carboxylic acid 1-Methyl-3- [4- (3-methyl-1,2,4-oxadiazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6- 4-methoxybenzylamide methyl 2-chloro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 2-Chloro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 1-Methyl-3- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-2-hydroxy-4- [ 6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 2-Hydroxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 01-1699-03 -C 302 methyl 2-methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 2-methyl-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (benzo [1,3] dioxole- 1-methyl-2,4-dioxo-3- (pyridine-4-methyl) -1,2,3,4-tetrahydroquinazinecarboxylic acid 5-ylmethyl) amide 1-Methyl-2,4-dioxo-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazinecarboxylic acid 4-methoxybenzylamide 1-methyl-2,4-dioxo-3- (pyridin-4-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxybenzylamide methyl-4- [6- (3-methoxybenzylcarbamoyl) - 1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 4- [6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-4- [1-methyl-6- (4 -methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 4- [1-methyl-6- (4-methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-4- [1-methyl-2,4- Dioxo-6- (4-trifluoromethoxybenzylcarbamoyl) -1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate methyl 4- [6- (4-fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1, 4-Dihydro-2H-quinazolin-3-yl-ethyl] -benzoate 4- [6- (4-Fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 01-1699-03 -C 303 Methyl 4- {6 - [(benzofurazan-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate 4- {6 - [(benzofurazan-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl [benzoic acid methyl-4- [6- Methyl 4- [1-ethyl-6- (4-methoxybenzylcarbamoyl) -2,4-dioxo (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 4- [1-ethyl-β- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (pyridin-4-ylmethyl) amide 3- (4- methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide 3- (4-hydroxybenzyl) -1-methyl-2,4 dioxo -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide 3- (4-cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4 1-methyl-2,4-dioxo-3- (3-pyridin-4-yl-allyl) -1,2,3,4-tetrahydroquinazoline-6-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide methyl 4- [1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl [benzoate] 4- {1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) -carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} -phenyl) -acetate 01-1699-03-CE 304 (4- {1-Mesyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} phenyl) acetic acid methyl-4 - {1-Methyl-2,4-dioxo-6 - [(1-oxypyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinolin-3-ylmethyl) benzoate 4- {1-methyl-2,4-dioxo-6 - [(1-oxypyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl- {6 - [(1 3-benzodioxol-5-ylmethyl) carbamoyl] -3-benzyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-1-yl} acetate [6 - [(1,3-benzodioxol-5- methylmethyl) carbamoyl] -3-benzyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl} acetic acid methyl-4- {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl} -benzoate 4- {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid 3-Benzyl-1-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid 4-sulfamoyl-benzylamide [3- (pyridin-4-ylsulfanyl) -propyl] -amide 3-Benzyl-1-methyl-2,4-dioxo-1,2-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quazoline-6-carboxylic acid (4-morpholin-4-yl-butyl) -amide 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (1-benzyl-piperidin-4-yl) -amide, 3,4-tetrahydroquinazoline-6-carboxylic acid, 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-hydroxybenzylamide 01-1699-03 -C 305 ethyl (4 - {[(3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carbonyl) amino] methyl} phenoxy) acetate (4- {[(3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonyl) amino] methyl} phenoxy) acetic acid 3-Benzyl-1-methyl-2,4-dioxo 4-dimethylcarbamoylmethoxybenzylamide 3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (3-phenylalyl) amide -1,2,3,4-tetrahydroquinoline-6-carboxylic acid 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-cyanobenzylamide 4 - {[(3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-β-carbonyl) amino] methyl} benzoic acid 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-dimethylcarbamoyl-benzylamide 3- (4-Dimethylaminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- [4- (N-Methylsulfonylamino) -benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide t-butyl- {5- [6 - (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] pyridin-2-yl} carbamate 3- (6-Amino-pyridin-3-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-o-carboxylic acid 4-methoxybenzylamide (1,3-benzodioxol-5-ylmethyl) 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [2,3-d] pyrimidine-6-carboxylic acid amide 01-1699-03 -C 306 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid (1, 3-benzodioxol-5-ylmethyl) -amide 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 3-benzodioxol-5-ylmethyl) amide 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide (1,3-benzodioxole- 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 5-ylmethyl) amide methyl-4- [6- (4) 1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoate t-butyl-4- [6- (4- (2-methoxybenzylcarbamoyl) -1,4-dihydro-2H) benzylcarbamoyl) -l-methyl-2,4-dioxo-l, 4-dihydro-2H-pyrido [3,4-d] pyrimidine-3-ylmethyl] benzoate 4- C 6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide 3-Benzyl-1-methyl-6- (3-phenylpropionyl) -1H-quinazoline-2,4-dione 01-1699-03 -C 307 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (E) -3-pyridin-4-ylalyl ester (E) -3-pyridine-3- 3-Benzyl-1-methyl-2,4-dioxo-1,2,4,4-tetrahydroquinazoline-6-carboxylic acid ylalyl ester 3-Benzyl-1-methyl-6- [2- (pyridin-4-ylsulfanyl) acetyl] -1H-quinazoline-2,4-dione 3- (4-Aminomethylbenzyl) -1-methyl-2,4-diaxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (2'-Cyanobiphenyl-4-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide -4 '- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] biphenyl-2-carboxylate 4 '- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] biphenyl-2-carboxylic acid ethyl-2-fluoro-4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 2-Fluoro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-dimethylaminoethyl ester 01-1699-03 -C 308 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -2-methylbenzoic acid 2-dimethylaminoethyl ester 1-methyl-2,4-dioxo-3- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) benzyl] 4-methoxybenzylamide -1,2,3, 4-tetrahydroquinazoline-6-carboxylic acid {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylphenyl} acetic acid (1,3 1-methyl-3- (1-naphthalen-1-ylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid -benzodioxol-5-ylmethyl) amide 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid (pyridine-4- 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxypyridin-4-ylmethyl) amide 3- (3- ylmethyl) amide 3- (3-fluorobenzyl) -1-methyl-2,4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) -amide -dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide 1-ethyl-3- (3-methoxybenzylamide) 3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 01-1699-03 -C 309 1-Ethyl-3- (3-fluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide 3- (4- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide) (2-methoxy-pyridin-4-ylmethyl) -amide Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide 3- (3,4-difluorobenzyl) -1-methyl- 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1, 2,4'-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide 3- (3-chloro-4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4, 2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide -tetrahydroquinazoline-6-carboxylic acid 3- (3-Chloro-4-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethylbenzoate (2-hydroxyethyl) trimethylammonium calcium salt 4- [6- (4- methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4- 3- (4-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (pyridin-4-ylmethyl) amide 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide 01-1699-03 -C 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide 3 (Pyridin-3-ylmethyl) amide 3 - (4-chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide 3- (4-Chloro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxy-benzylamide (2-methoxy-pyridin-4-ylmethyl) -amide 3- (4-Chlorobenzyl) -1-methyl-2-fluoro-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide 4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid t-butyl-1- {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4 dihydro-2H-quinazolin-3-ylmethyl] -phenyl} cyklopropánkarboxyiát 1- {4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} cyclopropanecarboxylic acid 3-Benzyl-6-benzylsulfanyl-1-methyl-1H-quinazoline-2,4-dione 3-benzyl-1-methyl-6-phenylmethanesulfinyl-1 H-quinazoline-2,4-dione 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-3-benzyl-1-methyl-6-phenylmethanesulfonyl-1H-quinazoline-2,4-dione t-butoxycarbonylmethyl ester -2H-quinazolin-3-ylmethyl] benzoic acid 01-1699-03-CE 311 4- [6- (4-Methoxy-benzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethylbenzoic acid dimethylaminomethylpropyl ester 4- [6- (4-methoxybenzylcarbamoyl) dimethylaminodimethylpropyl ester 1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2-dimethylaminoethyl ester chloromethyl 4- [6- (4-methoxybenzylcarbamoyl) ester 1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid 2-t-butoxycarbonylamino-3-methyl- (1-butanoyloxymetylester) ester 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 4- [6- (4-methoxybenzylcarbamoyl) -1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid hydrochloride (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 2- (2-t-butoxycarbonylamino-3-methylbutanoylamino) -3-methylbutanoyloxymethyl 4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazoline- 3-ylmethyl] benzoic acid 4- (6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl) 2- (2-amino-3-methylbutanoylamino) -3-methylbutanoyloxymethyl ester benzoic acid. A compound of formula I according to claim 1, which is: 01-1699-03 -C 312 4- (6- (4-Methoxybenzylcarbamdyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl) benzoic acid (1,3-benzodioxole) 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-6-carboxylic acid -5-ylmethyl) amide 4- [6- (4-Fluorobenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 1-Methyl-2,4-dioxo-3- [4- (5-oxo-4,5-dinydro-1,2,4-oxadiazol-3-yl) benzyl] 4-methoxybenzylamide -1,2,3, 4-tetrahydroquinazoline-6-carboxylic acid 4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid hemicalcium salt of methyl-4 - [6- (4-benzylcarbamoyl) -i-methyl-2,4-dioxo-l, 4-dihydro-2H-pyrido [3,4-d] pyrimidine-3-ylmethyl] benzoate 4- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 1-methyl-2,4-dioxo-3- [4- (2H-tetrazol-5-yl) benzyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl-2-hydroxy- 4- [6- (4-methoxy-benzylcarbamoyl) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- (4-Chlorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide 4- (6 - ((1,3-Benzodioxol-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinolin-3-ylmethyl [benzoic acid 2-Hydroxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 01-1699-03-CE 313 methyl 4- [6- (3-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide 4-pyridylmethyl-3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate methyl 4 - {6 - [(1,3-benzodioxol-5-ylmethyl) carbamoyl] -1 methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate 1-Methyl-3- [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6- 4-methoxybenzylamide carboxylic acid 1-Methyl-3- [4- (3-methyl-1,2,4-oxadiazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6- 4-methoxybenzylamide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H] quinazolin-3-ylmethyl] benzoic acid 1- {4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl} cyclopropanecarboxylic acid 4-pyridylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate 3- (4-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxybenzylamide 01-1699-03-CE 314 3- (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Dimethylcarbamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide (2 3- (4-Bromobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-3-ylmethyl) amide 3- (4-bromobenzyl) -methoxypyridin-4-ylmethyl amide (3,4-Difluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid benzo [1,3] dioxol-5-ylmethyl-3-benzyl-1- 3-Benzyl-1-methyl-2,4-dioxo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (benzo [1,3] dioxol-5-ylmethyl) -amide 2,3,4-tetrahydroquinazoline-6-carboxylic acid 1-Methyl-3- (4-methylcarbamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (3-Fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 4- [6- (4-hydroxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid methyl-4- [6- (4-fluorobenzylcarbamoyl) - l-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- (4-Chlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide 01-1699-03 -C 315 1-Methyl-3- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 4-pyridylmethyl-3- (benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate methyl 4- [6- (4-methoxybenzylcarbamoyl) ) -l-methyl-2,4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydroquinazinecarboxylic acid 4-methoxybenzylamide 3- (4-Aminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 2-Methoxy-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 1-Methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 1-Methyl-2,4-dioxo-3- (4-sulfamoylbenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 3- (4-Fluorobenzyl) amide 3- (4-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) amide -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 01-1699-03 -C 316 3- (4-Methoxy-benzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (pyridin-4-ylmethyl) -amide 2-Methyl-4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 4- {1-Methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoic acid 3- (3-Fluoro-4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamine 4- [1-ethyl-6- (4-methoxybenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid (benzo [1,3] dioxol-5-ylmethyl) 3- (Benzo [1,3] dioxol-5-ylmethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid amide 3- (2'-Cyano-biphenyl-4-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 4- [1-methyl-6- (4-methylsulfanylbenzylcarbamoyl) -2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 4- {6 - [(benzofurazan-5-ylmethyl) carbamoyl] -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl [benzoic acid methyl-2-methyl-4- [6- (4-benzylcarbamoyl) -l-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- (4-Acetylaminobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide 01-1699-03 -C 317 3- (Benzo [1,3] dioxol-5-ylmethyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (benzo [1,3] dioxol-5-ylmethyl) amide -6-carboxylic acid 3- (4-Dimethylcarbamoylmethylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide benzo [1,3] dioxol-5-ylmethyl-3-benzyl -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H- quinazolin-3-ylmethyl] phenyl} acetic acid (4- {1-methyl-2,4-dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl (phenyl) acetic acid 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl- {4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo] 3- (3-fluorobenzyl) -1-methyl-2,4-dioxo-1,2,3-1,4-dihydro-2H-quinazolin-3-ylmethyl] phenyl] acetate (pyridin-4-ylmethyl) amide 2,4-dioxo-3- (thien-2-ylmethyl) -1,2,3,4-tetrahydroquinazoline-6- (4-tetrahydroquinazoline-6-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) amide) carboxylic acid 1-methyl-3- (4-methylsulfamoylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide methyl-4- {1-methyl-2,4- dioxo-6 - [(pyridin-4-ylmethyl) carbamoyl] -1,4-dihydro-2H-quinazolin-3-ylmethyl} benzoate 2-Fluoro-4- [6- (4-methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 1-1699-03 -C 318 3- (4-Cyanobenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxybenzylamide 4- [6- (3-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [3,4-d] pyrimidin-3-ylmethyl] benzoic acid hemi-magnesium salt 6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoic acid 4- [6- (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid 3- [4- (N-Methylsulfonylamino) benzyl] -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide ethyl-2-fluoro-4- [6 (4-Methoxybenzylcarbamoyl) -1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] benzoate 3- (4-Dimethylsulfamoylbenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide and (benzo 1,3] dioxol-5-ylmethyl) amide 3 - (4-methoxybenzyl) -1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid. 17. Intermediate of formula III: HO 'N' f H O σπ) 01-1699-03 -C 319 wherein R ³ has the same meaning as previously defined for the compound of formula I. wherein R ¹ and R ³ have the same meaning as the compound of formula I. defined for 19. A process for the preparation of a compound of formula I: wherein R ² , R ³ , Z ¹ , A, n and m are as defined in claim 1, R ¹ is hydrogen, X ¹ , X ² and X ³ are CH, Y is oxygen, Z is NR ⁷ and W is an oxygen atom comprising the reaction of a compound of formula II: (Π) with pyridine and a compound of formula V: 01-1699-03 -C 320 O = C = NR ³ (V) wherein R ³ is as defined in claim 1, to give a compound of formula VI: (VI) wherein R ³ is as defined above, followed by reaction of a compound of formula VI in the presence of lithium hydroxide to give a compound of formula III, wherein R ³ is as defined above: (DO) said compound of formula III reacts in the presence of an acid activator such as TOTU with a compound of formula VII: (R). , NH (dr) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cyclo01-1699-03-Ce 321 alkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are as defined in claim 1 to give a compound of formula I wherein R ¹ is hydrogen, X ¹ , X ² and X ³ are CH, Y is O, Z is NR ⁷ , W is O, and A, R ² , R ³ , Z ¹ , and m are as defined above. A process for the preparation of a compound of formula I wherein R ¹ , R ² , R ³ , A, Z ¹ , X ² and X ³ are CH, is NR ⁷ , m and n are as defined in claim 1, X ¹ , W is an oxygen atom, Y is an oxygen atom, and Z is characterized by the formula VI: by reacting a compound of general formula (VO where R ³ is as defined in claim 1) in the presence of a base with compound VIII of formula XR ¹ , wherein R ¹ is as defined in claim 1 and X is a leaving group such as a halogen atom to obtain the compound of formula IX: 01-1699-03 -C 322 (ix) wherein R ³ and R ¹ are as defined above, said compound of formula IX is reacted in the presence of lithium hydroxide to obtain a compound of formula IV: where R ¹ a R ³ are the same (TV) as defined above, said compound of formula (IV) reacts with a compound of formula (VII) in the presence of an acid activator such as TOTU: (VH) to give a compound of formula I: wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , and m are as defined in claim 1, 01-1699-03-CE 323 wherein R ¹ , R ² , R ³ , A, Z ¹ , m and n are as defined in claim 1, X ¹ , X ² and X ³ are CH, W is O, Y is O and Z is NR ⁷ . A process for the preparation of R ¹ , R ² , R ³ , W, X ¹ , X ² , X ³ as defined in claim 1, Y characterized by formula I of a compound of formula I, wherein: A, Z ¹ , m and n are the same as oxygen and Z is NR ⁷ , by the compound of the general formula wherein R ¹ is hydrogen, and R ² , R ³ , W, X ¹ , X ² , X ³ , A, Z ¹ , m and n are as defined in claim 1, reacting in the presence of a base with a compound of formula XR ¹ wherein R ¹ is as defined in claim 1 and X is a leaving group such as a halogen atom to yield compounds of formula I wherein R ¹ is as defined in claim 1. A process for the preparation of a compound of formula I wherein X ¹ , X ² and X ³ are CH, W is O, Y is O, Z is NR ⁷ , R ³ is hydrogen and R ¹ , R ² , A, Z ¹ , m and n are the same as defined in claim 1, 01-1699-03 -C 324 characterized by the formula XI, the compound of which R ¹ is as defined above, is reacted with aluminum chloride in a solvent such as benzene to give a compound of formula XII: (XU) wherein R ¹ is as defined above, said compound of formula in the presence of lithium hydroxide and a mixture of obtaining a compound of formula XIII: XII reacts dioxane / water to (ΧΠΓ) where R ¹ is as defined above, 01-1699-03-CE 325 said compound of general formula in the presence of an acid activator of formula VII: of formula XIII is reacted as TOTU, with compound (VH) wherein R ⁷ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms in each alkyl moiety, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are as defined in claim 1, to give a compound of formula XIV, pgv) wherein X ¹ , X ² and X ³ are CH, W is O, Y is an oxygen atom, and R ⁷ , R ¹ , A, R ² , Z ¹ , and m are as defined above. 23. A process for the preparation of a compound of formula (I), comprising the step of: Y ABOUT QOV) 01-1699-03 -C 326 wherein X ¹ , X ² and X ³ are CH, W is O, Y is O, and R ⁷ , R ¹ , A, R ² , Z ¹ , m and n are as defined in claim 1, is reacted with a compound of formula XR ³ wherein R ³ is as defined in claim 1 and X is a leaving group such as a halogen atom to give a compound of formula I: wherein X ¹ , X ² and X ³ are CH, W is O, Y is O, and R ⁷ , R ¹ , A, R ² , R ³ , Z ¹ , m and n are the same as defined in claim first A process for the preparation of a compound of formula I wherein X ¹ , X ² and X ³ are CH, W is O, Y is O and Z is O, wherein the compound of formula III: wherein R ³ is as defined in claim 1, reacts with a compound of formula XVI: 01-1699-03-CE (Xvi) wherein A, R ² , Z ¹ , m and n are the same as defined in claim 1. 1, to obtain a compound of formula XVII: (XVH) wherein A, R ² , R ³ , Z ¹ , m and n are as defined above, X ¹ , X ² and X ³ are CH, and W is an oxygen atom. 25. A method of preparation characterized by the formula XVII: a compound of formula I, wherein the compound of formula (XVII) wherein A, R ² , R ³ , Z ¹ , m and n are as defined in claim 1, X ¹ , X ² and X ³ are CH, and W is an oxygen atom, reacts in the presence of a base with a compound of formula XR ¹ wherein R ¹ is as defined in claim 1 and X is a leaving group such as a halogen atom to give a compound of formula I: 01-1699-03 -C 328 wherein A, R ¹ , R ² , R ³ , Z ¹ , m and n are as defined above, X ¹ , X ² is CH and W is oxygen. A process for preparing a compound of formula I, and X ³ is CH, X ¹ is nitrogen, Z is oxygen, oxygen, R ¹ is hydrogen, W is oxygen, and A, Z ¹ , and m are as defined in claim 1, comprising the step of: a compound of formula XIX: (XIX) X ³ are wherein X ² , Y is 3 ² , R ³ , which is reacted with pyridine and a compound of formula V = wherein R ³ is as defined in claim 1 to form = NR ³ , a compound of formula XX: (XX) wherein R ³ is as defined above, 01-1699-03-CE 329 said compound of formula XX is reacted in the presence of potassium permanganate to give a compound of formula XXI: (XXI) wherein R ³ is as defined above, said compound of formula XXI is reacted in the presence of SOCl 2 and optionally a solvent to obtain a compound of formula XXII: H (XXII) wherein R ³ is as defined above, said compound of formula XXII is reacted with a compound of formula XVI: (£ *), AJ / OH (XVI) wherein A, R ² , Z ¹ , m and n are the same as defined in the claim 1, to obtain a compound of formula XXIV: 01-1699-03 -C 330 (XXIV) wherein X ² and X ³ are CH and A, n, m, Z ¹ , R ² and R ³ are as defined above. A process for the preparation of a compound of formula I, wherein X ² and X ³ are CH, X ¹ is nitrogen, Z is -NR ⁷ , wherein R ⁷ is as defined for the compound of formula I, W is an oxygen atom e and Y is an oxygen atom, comprising the step of identifying a compound of formula XXV: reacted in a first step with N, N'-dimethylformamide dimethylacetal boiling in dimethylformamide and in a second step reacted with N-iodosuccinimide to give a compound of formula XXVI: followed by treatment with cuprous ethyl acrylate and a base to react a compound of formula XXVI in the presence of palladium diacetate, an iodide to obtain a compound of formula XXVII; 01-1699-03-CE 331 (XXVII) followed by reaction of a compound of formula XXVII in the presence of lithium hydroxide to give a compound of formula XXVIII: said compound of formula XXVIII either reacts in the presence of an acid activator such as TOTU with a compound of formula VII: (VB) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to obtain a compound of formula XXIX: 01-1699-03 -C 332 my I (XXIX) wherein A, R ² , R ⁷ , Z ¹ , m and n are as defined above, and X ² and X ³ are each -CH, or react in the first step with aluminum chloride in the presence of benzene and in the second step in the presence of an activator an acid such as TOTU with a compound of formula VII: (VH) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are defined in the description of the invention, to give a compound of formula XXX: (XXX) wherein A, R ² , R ⁷ , -CH, From ¹ , m and n are as defined above and X ² and X ³ are each followed by reaction of a compound of formula R ³ -X, where R ³ is the same of formula XXX with a compound as defined for 01-1699-03-CE 333 a compound of formula I, in the presence of a base, to obtain a compound of formula XXXI: A process for preparing a compound of formula I wherein X ¹ and X ³ are CH, X ² is nitrogen, Z is -NR ⁷ wherein R ⁷ is as defined for the compound of formula I, W is oxygen and Y is Oxygen, comprising the step of: (ΧΧΧΠ) reacts in the first step with selenium dioxide in the presence of an acid activator, in the second step with dimethylhydrazine and in the third step with N, N'-dimethylformamide dimethyl acetal boiling in dimethylformamide, to obtain a compound of formula XXXIII: (ΧΧΧ3Π) followed by an acrylate reaction in the presence of a compound of formula XXXIV: of the compound of formula XXXIII palladium diacetate with methyl recovery 01-1699-03 -C 334 (xxxrv) followed by reaction of the compound of formula and acetic acid to give the compound XXXIV with chlorobenzene of formula XXXV: followed by reaction of a compound of formula XXXV in the presence of a base to give a compound of formula XXXVI: (XXXVI) said compound of formula XXXVI: either react in the presence of an acid activator such as TOTU with a compound of formula VII: (VH) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, arylalkyl 01-1699-03-CE 335 having 1 to 6 carbon atoms in the alkyl moiety, a cycloalkyl group, an aryl group, and a heteroaryl group, and A, R ² , Z ¹ , m and n are as defined in the disclosure, to give a compound of formula XXXVII: wherein A, R ² , R ⁷ , Z ¹ , m and n are as defined above and X ¹ and X ³ are each -CH, or reacted in the first step with aluminum chloride in the presence of benzene and in the second step in the presence of an acid activator such as TOTU , with a compound of formula VII: (VB) wherein R ⁷ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, cycloalkyl, aryl and heteroaryl, and A, R ² , Z ¹ , m and n are as defined in the description of the invention, to obtain a compound of formula XXXVIII: (XXXVHI) 01-1699-03 -C 336 wherein A, R ² , R ', Z ¹ , m and n are as defined above and X ¹ and X ³ are each -CH, followed by reaction of a compound of formula XXXVIII with a compound of formula R ³ -X, wherein R ³ is the same as defined for a compound of formula I, in the presence of a base, to give a compound of formula xxxix: (XXXIX) A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient. Use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for treating a disease or condition comprising treatment by inhibiting a matrix metalloprotease type 13. Use according to claim 30, wherein the disease being treated is arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease (COP), COPD with age (ARMD) and cancer. The use of claim 31, wherein the disease is arthritis. The use of claim 31, wherein the disease is osteoarthritis. 01-1699-03-CE 337 The use of claim 31, wherein the disease is rheumatoid arthritis. 35. A method of treating a disease or condition comprising treatment by inhibiting MMP-13, comprising administering to a patient an effective amount of a compound of any one of claims 1 to 16. The method of claim 35, wherein the disease or condition is selected from the group consisting of arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma. , chronic obstructive pulmonary disease (COPD), age-related macular degradation (ARMD), and cancer. 37. The method of claim 35, wherein the disease is arthritis. 38. The method of claim 35, wherein the disease is osteoarthritis. 39. The method of claim 35, wherein the disease is rheumatoid arthritis.